1-Morpholinocarbonyl imidazoles

ABSTRACT

Novel imidazole compounds, pesticidal compositions and methods of using them, and their preparation are described. The compounds have the formula ##STR1## in which X is oxygen or sulphur, R 3  is hydrogen, alkyl, alkenyl or optionally substituted alkylthio, alkenylthio, aralkylthio, alkoxyalkyl or alkylthioalkyl, R 4  is alkyl or cycloalkyl, and R 1  and R 2  are each lower alkyl or alkenyl, R 1  is lower alkyl and R 2  is alkoxyalkyl or haloalkyl, or R 1  and R 2  together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclic ring; and salts thereof. Novel compounds are of particular value against insects e.g. aphids, and against other pests, e.g. acarids.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a division of application Ser. No. 523,774,filed Nov. 14, 1974, now U.S. Pat. No. 3,996,366; which is acontinuation-in-part of application Ser. No. 417,991, filed Nov. 21,1973, now U.S. Pat. No. 3,940,484; and which in turn is acontinuation-in-part of application Ser. No. 311,009, filed Nov. 30,1972, now U.S. Pat. No. 3,868,458.

The invention relates to new chemical compounds, pesticidal compositionscontaining the new compounds as active ingredient, and the use of thenew compounds to control pests.

According to one feature of the invention there is provided a new groupof compounds which may be represented by the general formula ##STR2## inwhich X is oxygen or sulphur, R³ is hydrogen, alkyl, alkenyl oroptionally substituted alkylthio, alkenylthio, aralkylthio, alkoxyalkylor alkylthioalkyl, R⁴ is alkyl or cycloalkyl, and (a) R¹ and R² are eachlower alkyl or lower alkenyl (b) R¹ is lower alkyl and R² is alkoxyalkylor lower haloalkyl, or (c) R¹ and R², together with the nitrogen atom towhich they are attached, form a heterocyclic ring, optionally containing1 to 4 lower alkyl substituents attached to carbon atoms of theheterocyclic ring, selected from morpholino, thiamorpholino,1-pyrrolidinyl and 1-piperidino; and salts thereof.

Of these compounds a particular group is one in which X is oxygen orsulphur, R³ is hydrogen, alkyl, alkenyl, alkylthio, alkenylthio,aralkylthio or alkoxyalkyl, R⁴ is alkyl or cycloalkyl, and (a) R¹ and R²are each lower alkyl or lower alkenyl, (b) R¹ is lower alkyl and R² isalkoxyalkyl or lower haloalkyl, or (c) R¹ and R², together with thenitrogen atom to which they are attached, form a heterocyclic ring,optionally containing 1 to 4 lower alkyl substituents attached to carbonatoms of the heterocyclic ring, selected from morpholino,thiamorpholino, 1-pyrrolidinyl and 1-piperidino.

A further group of compounds is one in which X is oxygen or sulphur, R³is optionally substituted alkylthio, alkenylthio, aralkylthio,alkoxyalkyl or alkylthioalkyl, R⁴ is alkyl or cycloalkyl and (a) R¹ andR² are each lower alkyl or lower alkenyl (b) R¹ is lower alkyl and R² isalkoxyalkyl or lower haloalkyl, or (c) R¹ and R² together with thenitrogen atom to which they are attached, form a heterocyclic ring,optionally containing 1 to 4 lower alkyl substituents attached to carbonatoms of the heterocyclic ring, selected from morpholino,thiamorpholino, 1-pyrrolidinyl and 1-piperidino; and salts thereof. Ofthese compounds a particular group is one in which R³ is alkylthio,alkenylthio, aralkylthio or alkoxyalkyl.

A preferred group of compounds is one in which (a) R¹ is methyl and R²is lower alkyl or lower alkenyl, (b) R¹ and R² are both ethyl, propyl orallyl, or (c) R¹ and R², together with the nitrogen atom to which theyare attached form a heterocyclic ring, optionally containing 1 to 4lower alkyl substituents attached to carbon atoms of the heterocyclicring, selected from morpholino, thiamorpholino, 1-pyrrolidinyl and1-piperidino. Preferred compounds are often those in which X in theabove general formula is oxygen.

The radical R³ may have a straight or branched chain and may contain,for example, up to 10 carbon atoms. Thus R³ may be, for example,hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,sec.butyl, tert.butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl,1,1-diethylpropyl, n-octyl, 2-ethylhexyl, n-nonyl, n-decyl, allyl,1-propenyl, 3-butenyl. Most suitably R³ is hydrogen, or lower alkyl suchas propyl, isopropyl, n-butyl, sec.butyl, isobutyl, tert.butyl andespecially methyl and ethyl.

R³ can also be optionally substituted alkylthio, alkenylthio,aralkylthio, alkoxyalkyl or alkylthioalkyl. An optionally substitutedalkylthio radical can be branched or unbranched, and preferably contains1 to 6 carbon atoms, especially 1 to 4 carbon atoms and the mostpreferred radicals are methylthio and ethylthio. The alkylthio group canbe substituted with one or more substituent such as one or more haloatoms, an alkoxy group, an alkoxycarbonyl group, an alkylthio group, analkenyloxy group or a dialkylamino group. Examples of these substituentsinclude chloro, bromo, fluoro, methoxy, ethoxy, methoxycarbonyl,ethoxycarbonyl, methylthio, ethylthio, vinyloxy, dimethylamino anddiethylamino.

When R³ is an optionally substituted alkenylthio radical it can, forinstance, contain from 2 to 6 carbon atoms, preferably from 2 to 4carbon atoms. When the radical is substituted preferred substituents areone or more halogen atoms, such as one or two halogen atoms, forexample, bromo, fluoro and especially chloro.

When R³ is an optionally substituted aralkylthio radical it can be, forexample, 2-phenylethylthio and is preferably benzylthio or benzylthiosubstituted with one or more substituent such as, for example, alkylespecially methyl, nitro, alkoxy especially methoxy, trifluoromethyl orhalo, especially chloro. There are most suitably one or two substituentson the phenyl ring.

When R³ is an optionally substituted alkoxyalkyl or alkylthioalkylradical it preferably contains 2 to 5, for example 2 to 4, carbon atoms.

Examples of such radicals are methylthio, ethylthio, propylthio,isopropylthio, n-butylthio, sec.butylthio, n-pentylthio, isopentylthio,hexylthio, methoxymethylthio, ethoxycarbonylmethylthio,methylthiomethylthio, vinyloxyethylthio, dimethylaminoethylthio,allylthio, 2-methylallylthio, 2-chloroprop-2-enylthio, but-2-enylthio,benzylthio, 4-chlorobenzylthio, 2,4-dichlorobenzylthio,2-methylbenzylthio, 2,4-dimethylbenzylthio,2-methyl-4-chloro-benzylthio, 3-trifluoromethylbenzylthio,3-nitrobenzylthio, 2-methoxybenzylthio, 4-methoxybenzylthio,methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl ormethylthiomethyl.

The radical R⁴ is alkyl or cycloalkyl and may contain, for example, upto 10 carbon atoms. Thus when R⁴ is alkyl it may have a straight orbranched chain, may be a primary, secondary or tertiary radical, forexample, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec.butyl,tert.butyl, 1-methylbutyl, 1-ethylpropyl, n-pentyl, isopentyl,tert.pentyl, n-hexyl, 1,1,2-trimethylpropyl, n-heptyl,1,1-diethylpropyl, 2,3,3-trimethylbut-2-yl, n-octyl, 2-ethylhexyl,n-nonyl or n-decyl. Preferred values of R⁴ when it is an alkyl group,are tert.butyl, sec.butyl, propyl, 1-ethylpropyl, isopropyl andtert.pentyl. When R⁴ is cycloalkyl it may contain, for example, up to 8,and more preferably from 3-7, carbon atoms in the cyclo ring. Thecycloalkyl group may optionally contain one or more substituents on thering, for example, one or more lower alkyl (especially methyl)substituents. A lower alkyl substituent is preferably in the 1-position,that is, it is attached to the cycloalkyl carbon atom joined to theimidazole ring. A further preferred group contains a lower alkyl(especially methyl) substituent in the 1-position and in addition one ormore lower alkyl (especially methyl) substituents in other positions onthe ring. When there is more than one substituent on the cycloalkylgroup they may be the same or different. Thus, for example, typicalvalues for R⁴ are cyclopropyl, 1-methylcyclopropyl, 2-methylcyclopropyl,2,2-dimethylcyclopropyl, cyclobutyl, 1-methylcyclobutyl, cyclopentyl,1-methylcyclopentyl, 1-ethylcyclopentyl, 2- 3- or 4-methylcyclopentyl,cyclohexyl, 1-methylcyclohexyl, 11 -methylcyclohexyl containing 1, 2 or3 further methyl substituents such as for example1,3-dimethylcyclohexyl, 1,4-dimethylcyclohexyl,1,3,3-trimethylcyclohexyl; 1-ethylcyclohexyl, 2- 3- or4-methylcyclohexyl, 2,4-dimethylcyclohexyl, 2- 3- or 4-ethylcyclohexyl,cycloheptyl or cyclooctyl. Preferably, when R⁴ is cycloalkyl, itcontains five or six carbon atoms in the cyclo ring and is cyclopentyloptionally containing one or more methyl substituents or cyclohexyloptionally containing one or more methyl substituents. Specific examplesinclude cyclopentyl, 1-methylcyclopentyl, cyclohexyl,1-methylcyclohexyl, 1,3-dimethylcyclohexyl, 1,3,3-trimethylcyclohexyl.

When the group NR¹ R² is an acyclic group both R¹ and R² may have astraight or branched chain. Preferably (a) R¹ and R² are the same ordifferent and are lower alkyl or lower alkenyl; examples of lower alkylare methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec.butyl,tert.butyl, n-pentyl, isopentyl, n-hexyl or n-heptyl; lower alkenyl maycontain, for example, 2 to 4 carbon atoms, especially allyl; or (b) R¹is lower alkyl and R² is alkoxyalkyl, containing for example from 3 to 6carbon atoms such as for example 2-methoxyethyl, 2-ethoxyethyl or3-ethoxypropyl, or lower haloalkyl containing for example from 1 to 6carbon atoms and substituted by one or more halogen atoms preferablyfluorine, chlorine or bromine, such as for example, 2-chloroethyl. It ispreferred that either (a) R¹ is methyl and R² is lower alkyl or (b) R¹and R² are both ethyl or propyl. A specially preferred group ofcompounds is that in which R¹ is methyl and R² is lower alkyl,preferably containing 1-4 carbon atoms and especially methyl.

As hereinbefore mentioned, when the group NR¹ R² is a heterocyclicgroup, it may contain 1-4 lower alkyl (especially methyl) substituentsattached to carbon atoms of the heterocyclic ring. Suchalkyl-substituted heterocyclic groups include, for example,2,6-dimethylmorpholino, 4-methyl-1-piperidino, 2-methyl-1-piperidino,2-6-dimethyl-1-piperidino and 2-ethyl-1-piperidino. When NR¹ R² isheterocyclic it is preferably morpholino, 1-pyrrolidinyl or 1-piperidinoand especially morpholino. Compounds in which the group NR¹ R² ismorpholino have the added advantage of low mammalian toxicity.

In utilising their pesticidal properties the compounds of the inventionare preferably used as the free base but may also be employed as an acidaddition salt which can be formed with an inorganic or organic acid, forexample hydrochloric, hydrobromic, hydroiodic, hydrofluoric, sulphuric,nitric, phosphoric, perchloric, sulphamic, formic, acetic,trichloroacetic, oxalic, picric, benzenesulphonic,dodecylbenzenesulphonic, p-toluenesulphonic, stearic, flavianic, embonicor tetraiodophthalaic acids. Such salts are pesticidally active byvirtue of the imidazole cation content of the salt.

We have found that the compounds of the present invention havepesticidal activity and, for example, can be used to combat insects. Thecompounds have activity against Diptera such as the larvae of the sheepblow fly, Lucilia sericata and species of Hemiptera. For example theyare of use against California red scale, Acridiella aurantii, theComstock mealybug, Pseudococcus comstocki and plant hoppers such as, forexample, the green rice leafhopper, Nephotettix cincticepts. They areespecially useful in controlling aphids such as Aphis fabae, Megouraviciae, Myzus persicae, Phorodon humuli, Eriosoma lanigerum, Brevicorynebrassicae and Acyrthosiphon pisum. The compounds also have acaricidalactivity against adults of the two-spotted mite, Tetranychus urticae andthe citrus red mite, Panonychus citri.

According to a further feature of the present invention there areprovided pesticidal, in particular insecticidal such as for exampleaphicidal, compositions which comprise as an active ingredient acompound of the present invention together with a diluent or carrier.The diluent or carrier may be a solid or a liquid, optionally inassociation with a surface-active agent, for example, a dispersingagent, emulsifying agent or wetting agent.

The compositions of the present invention may take any of the formsknown in the art for the formulation of pesticidal or insecticidalcompounds, for example solutions, aqueous dispersions, aqueousemulsions, dusting powders, dispersible powders, fumigants, emulsifiableconcentrates and granules. Such compositions include not onlycompositions in a suitable form for application but also concentratedprimary compositions which require dilution with a suitable quantity ofwater or other diluent before application. Dispersible powders andemulsifiable concentrates are typical examples of such primarycompositions.

As dispersions, the compositions comprise essentially a compound of theinvention dispersed in an aqueous medium. It is convenient to supply theconsumer with a primary composition which may be diluted with water toform a dispersion having the desired concentration; the primarycomposition may be in any one of the following forms. It may be providedas a dispersible solution which comprises a compound of the inventiondissolved in a water-miscible solvent with the addition of a dispersingagent. Alternatively it may be provided as a dispersible powder whichcomprises a compound of the invention and a dispersing agent. A furtheralternative comprises a compound of the invention in the form of afinely ground powder in association with a dispersing agent andintimately mixed with water to give a paste or cream. This paste orcream may if desired be added to an emulsion of oil in water to give adispersion of active ingredient in an aqueous oil emulsion.

Emulsions comprise essentially a compound of the invention dissolved ina water-immiscible solvent which is formed into an emulsion with waterin the presence of an emulsifying agent. An emulsion of the desiredconcentration may be formed from a primary composition of the followingtypes. A concentrated stock emulsion may be supplied comprising acompound of the invention in combination with an emulsifying agent,water and a water-immiscible solvent. Alternatively there may besupplied an emulsifiable concentrate comprising a solution of a compoundof the invention in a water-immiscible solvent containing an emulsifyingagent.

A dusting powder comprises a compound of the invention intimately mixedand ground with a solid pulverulent diluent, for example kaolin.

A granular solid may comprise a compound of the invention associatedwith similar diluents to those which may be employed in dusting powders,but the mixture is granulated by known methods. Alternatively they maycomprise the active ingredient absorbed or adsorbed on a pre-formedgranular diluent for example fuller's earth, attapulgite and limestonegrit.

The concentration of the active ingredient in the primary compositionsof the present invention may vary widely and may be, for example, 5-95%w/w of the composition. The concentration of the active ingredient inthe compositions of the present invention for application to controlpests, especially insects such as aphids, is generally within the range0.001-10% w/w, especially 0.005-5% w/w.

According to a further feature of the present invention there isprovided a method for combating pests, especially insects, whichcomprises applying a compound of the present invention to the locus ofthe pests, i.e. the pests or their habitat. A particular embodiment ofthis feature is a method for protecting plants from insects, and inparticular aphids, which comprises applying a compound of the presentinvention to the locus of the plants, i.e., the plants or their habitat.

In combating pests the active compound can be applied on its own orpreferably as one of the compositions described above. Direct treatmentis often the preferred method, by for example, spraying, dusting orfumigation of plants infested with insects. Alternatively the activecompound can be applied to the soil in which plants are grown asgranules or as a root drench. In such instances the active compound isabsorbed by the roots of the plant and confers protection from theinsects. A suitable application rate of the compound of the presentinvention is generally within the range 0.005-10 lb/acre, more usually0.01-5 lb/acre. The compounds of the present invention may be used toprotect a variety of plants from aphids, for example ornamental plantssuch as roses, and crop plants such as fruit trees, leguminous crops,potatoes, hops, sugar beet, cotton, maize, rice and tobacco.

A composition of the invention may comprise as active ingredient morethan one compound of the general formula I and it may also comprise oneor more additional pesticide or, for example, a fungicide or insecticidefor example an organochlorine or organophosphorus insecticide.

The compounds of the present invention may be prepared by a processwhich comprises reacting an imidazole of the general formula ##STR3## inwhich R³ and R⁴ are as hereinbefore defined with a carbamoyl halide orthiocarbamoyl halide of the general formula Z-CXNR¹ R² (III) in whichR¹, R² and X are as hereinbefore defined and Z is halogen, for example,chlorine or bromine preferably chlorine. The reaction is suitablyeffected in the presence of an inert organic liquid as the reactionmedium, which is preferably a solvent for the reactants. Advantageouslythe reaction is effected in the presence of a suitable acid-bindingagent, for example a tertiary amine such as triethylamine or pyridine,in order to absorb the hydrogen halide produced in the reaction. Inpreparing the compounds by this route the reactants are preferablyreacted together at a temperature of from 0° to 120° C., for examplefrom 50° to 95° C. The salts of the invention can readily be prepared bytreatment of the product with acid by well known methods.

The imidazole compounds of formula II in which R³ is optionallysubstituted alkylthio, alkenylthio, aralkylthio, alkoxyalkyl oralkylthioalkyl and R⁴ is cycloalkyl or alkyl containing more than onecarbon atom are novel compounds.

Compounds of formula II in which R³ is optionally substituted alkylthio,alkenylthio or aralkylthio can be prepared by, for example, reacting analkali metal thiocyanate with an appropriate aminomethyl ketone of thegeneral formula

    R.sup.4 COCH.sub.2 NH.sub.2

to give a thiol of the following formula ##STR4## which in its turn, canbe alkylated, alkenylated or aralkylated according to well known methodsto give compounds of formula II. Alternatively, compounds of formula IIin which R³ is optionally substituted alkylthio, alkenylthio oraralkylthio can be prepared by reacting, in the presence of alkali, anα-haloketone of the general formula R⁴ COCH₂ Z in which Z is halogenatom with an S-alkylisothiouronium salt of the following formula##STR5## in which R³ is as defined immediately above and A represents asuitable anion, for example sulphate or halide.

Those compounds of formula II in which R³ is optionally substitutedalkoxyalkyl or alkylthioalkyl can be made by, for example, condensing analdehyde of the general formula R³ CHO in which R³ is optionallysubstituted alkoxyalkyl or alkylthioalkyl with an acyloxylated ketone ofthe general formula R⁴ COCH₂ B in which B is acyloxy, in the presence ofammonia.

The carbamoyl halides or thiocarbamoyl halides of the general formulaIII may be prepared by reacting a secondary amine of the general formulaHNR¹ R² with a carbonyl halide or thiocarbonyl halide of the generalformula CXZ₂ in which Z is preferably chlorine, in accordance with knownmethods.

The compounds of the present invention may also be prepared by a processwhich comprises reacting a carbamoyl halide or thiocarbamoyl halide ofthe general formula ##STR6## in which R³, R⁴ and Z are as hereinbeforedefined, Z being halogen preferably chlorine, with a secondary amine ofthe general formula HNR¹ R², R¹ and R² being defined hereinbefore. Thereaction is suitably effected in the presence of an inert organic liquidas the reaction medium, which is preferably a solvent for the reactants,at a temperature of from -5° to 50° C. Advantageously the reaction iseffected in the presence of a suitable acid-binding agent, for exampletertiary amine such as triethyl amine or pyridine.

The compounds of the general formula V are preferably prepared in situfrom the imidazoles of general formula II by reaction with a carbonylhalide or thiocarbonylhalide CXZ₂, in which Z is preferably chlorine,suitably in the presence of a solvent and acid-binding agent; thesecondary amine reactant then being added to the reaction product.

The compounds of the present invention may also be prepared by a processwhich comprises reacting a carbonylbisimidazole orthiocarbonylbisimidazole of the general formula ##STR7## in which R³, R⁴and X are as hereinbefore defined, with a secondary amine of the generalformula HNR¹ R² R¹ and R² being defined hereinbefore. The reaction issuitably effected in the presence of an inert organic liquid as thereaction medium, which is preferably a solvent for the reactants, at atemperature of, for example, from -5 to 50° C.

The compounds of the general formula VI are preferably prepared in situby reacting an imidazole of the general formula II with about 0.5molecular proportions of a carbonyl halide or thiocarbonyl halide CXZ₂in which Z is preferably chlorine; the secondary amine then being addedto this reaction product. The reaction is preferably effected in thepresence of a suitable acid-binding agent, for example a tertiary aminesuch as triethylamine or pyridine.

It will be appreciated that the reactions described above may giveeither or both of two isomeric products, depending on which nitrogenatom in the imidazole ring is substituted (the free hydrogen of theimidazole molecule of formula II can be associated with either of thering nitrogen atoms). The products of the present invention may beconveniently designated at 1-(N,N-disubstituted-carbamoyl orthiocarbamoyl)-2-R³ -4(5)-R⁴ -imidazoles. This designation correspondsto formula I which encompasses both of the isomeric forms. The currentstate of our knowledge indicates that the solid products of thereactions described above, after purification by conventional techniquessuch as crystallization, are obtained in many instances as substantiallypure 4-substituted compounds. The current state of our knowledge alsoindicates that the liquid products of the reactions described above,after isolation by conventional techniques such as distillation invacuo, are obtained in many instances substantially or predominantly inthe 4-substituted isomeric form. It will be appreciated that suchisomers may be designated as 1-(N,N-disubstituted-carbamoyl)-2-R³ -4-R⁴-imidazoles.

The following examples illustrate the invention.

EXAMPLE 1

To a stirred mixture of 173 g. 4-tert.butylimidazole, 205 ml.triethylamine and 300 ml. dry tetrahydrofuran was gradually added 167 g.dimethylcarbamoyl chloride. An exothermic reaction ensued, and the rateof addition of dimethylcarbamoyl chloride was adjusted so as to maintaina gentle boiling of the reaction mixture under reflux. When addition ofthe dimethylcarbamoyl chloride was complete, the reaction mixture wasboiled under reflux with stirring for 1 hour, and then cooled to roomtemperature. The reaction mixture was diluted with 200 ml. water andthen extracted with diethyl ether (2 × 200 ml.). The ethereal extractswere combined, dried over anhydrous sodium sulphate and evaporated. Theresulting residue was crystallized from light petroleum (b.p. 100° -120° C.) and recrystallized from di-isopropyl ether to give1-dimethylcarbamoyl-4(5)-tert.butylimidazole, m.p. 85° - 86° C. Thecurrent state of our knowledge indicates that this compound is1-dimethylcarbamoyl-4-tert.butylimidazole.

EXAMPLE 2

In an analogous manner to that described in Example 1, there wasprepared 1-dimethylcarbamoyl-4(5)-methylimidazole, m.p. 58° - 60° C.(crystallized from light petroleum b.p. 100° - 120° C. andrecrystallized from methylcyclohexane). The current state of ourknowledge indicates that this compound is1-dimethylcarbamoyl-4-methylimidazole.

EXAMPLE 3

A solution of 2.46 g. 4-tert.butylimidazole, 1.0 g. triethylamine and2.42 g. N-ethyl-N-methylcarbamoyl chloride in 20 ml. dry tetrahydrofuranwas boiled under reflux for 6.5 hours. The reaction mixture was cooledto room temperature and filtered to remove triethylamine hydrochloride.Solvent was removed from the resulting filtrate by evaporation underreduced pressure and the residue was distilled under reduced pressure togive 1-(N-methyl-N-ethylcarbamoyl)-4(5)-tert.butylimidazole, b.p. 99° -101° C./0.1 mm.

In an analogous manner to that described above, there were prepared thefollowing compounds.

1-dimethylthiocarbamoyl-4(5)-tert.butylimidazole, b.p. 140° - 141°C./1.0 mm.

1-(N-methyl-N-propylcarbamoyl)-4(5)-tert.butylimidazole, b.p. 120° -122° C./0.5 mm.

1-(N-methyl-N-heptylcarbamoyl)-4(5)-tert.butylimidazole, b.p. 154° -156° C./0.7 mm.

1-diallylcarbamoyl-4(5)-tert.butylimidazole, b.p. 120° - 121° C./0.2 mm.

1-(N-methyl-N-allylcarbamoyl)-4(5)-tert.butylimidazole, b.p. 126° - 128°C./1.0 mm.

1-dimethylcarbamoyl-2-ethyl-4(5)-methylimidazole, b.p. 85° C./0.15 mm.

1-dimethylcarbamoyl-4(5)-n-pentylimidazole, b.p. 120° C./0.09 mm.

1-dimethylcarbamoyl-4(5)-isobutylimidazole, b.p. 104° C./0.13 mm.

1-dimethylcarbamoyl-4(5)-isopropylimidazole, b.p. 98° C./0.13 mm.

1-dipropylcarbamoyl-4(5)-isobutylimidazole, b.p. 104° - 106° C./0.05 mm.

1-dipropylcarbamoyl-4(5)-isopropylimidazole, b.p. 108° C./0.12 mm.

1-dimethylthiocarbamoyl-4(5)-isopropylimidazole, b.p. 107° - 114°C./0.03 - 0.05 mm.

1-dimethylcarbamoyl-4(5)-(1-ethylpropyl) imidazole, b.p. 112° C./0.15mm.

1-dipropylcarbamoyl-4(5)-(1-ethylpropyl)imidazole, b.p. 100° - 106°C./0.25 - 0.03 mm.

1-dimethylcarbamoyl-2-methyl-4(5)-methylimidazole, b.p. 80° - 84°C./0.7 - 0.1 mm.

1-dimethylcarbamoyl-4(5)-isopropylimidazole, b.p. 98° C./0.13 mm.

1-dimethylthiocarbamoyl-2-ethyl-4(5)-methylimidazole, b.p. 128° - 130°C./0.3 mm.

1-dimethylcarbamoyl-4(5)-sec.butylimidazole, b.p. 95° C./0.04 mm.

1-(2,6-dimethylmorpholinocarbonyl)-4(5)-tert.butylimidazole, b.p. 154°C./1.0 mm.

The current state of our knowledge indicates that the 4(5) alkyl groupsof the imidazoles listed above are predominantly or substantially in the4-position.

EXAMPLE 4

A mixture of 5.52 g. 4-tert.butylimidazole, 6.1 g. triethylamine, 8.95g. morpholinocarbonyl chloride and 30 ml. dry tetrahydrofuran was boiledunder reflux for 5 hours. The reaction mixture was diluted with 100 ml.methylene dichloride, cooled to room temperature, and washed with waterto remove triethylamine hydrochloride. The resulting organic solutionwas dried over anhydrous magnesium sulphate and then evaporated todryness. The resulting solid residue was recrystallized from ethanol togive 1-morpholinocarbonyl-4(5)-tert.butylimidazole, m.p. 129° - 130° C.The current state of our knowledge indicates that this compound is1-morpholinocarbonyl-4-tert.butylimidazole.

EXAMPLE 5

A mixture of 5.0 g. 4-tert.butylimidazole, 4.4 g. triethylamine, 5.9 g.1-piperidinocarbonyl chloride and 30 ml. dry tetrahydrofuran was boiledunder reflux for 5.5 hours. The reaction mixture was cooled, filtered toremove triethylamine hydrochloride, and evaporated to dryness. Theresulting solid residue was recrystallized from petroleum (b.p. 62° -68° C.) to give 1-piperidinocarbonyl-4(5)-tert.butylimidazole, m.p.104° - 105° C.

The following compound was prepared in an analogous manner.

1-(1-pyrrolidinylcarbonyl)-4(5)-tert.butylimidazole m.p. 124° - 126° C.

The current state of our knowledge indicates that the tert.butyl groupin the above compounds is in the 4-position.

EXAMPLE 6

In an analogous manner to that described in Example 3, the followingcompounds were prepared.

1-dimethylcarbamoyl-4(5)-sec.butylimidazole, b.p. 114° - 122° C./0.1 mm.

1-(N-methyl-N-2-ethoxyethylcarbamoyl)-4(5)-tert.butylimidazole, b.p.137° - 138° C./0.4 mm.

1-dimethylcarbamoyl-4(5)-propylimidazole, b.p. 108° C./0.27 mm.

1-dimethylcarbamoyl-4(5)-butylimidazole, b.p. 109° C./0.1 mm.

1-morpholinocarbonyl-4(5)-sec.butylimidazole, b.p. 119° - 126° C./0.05mm.

1-morpholinocarbonyl-4(5)-isobutylimidazole, b.p. 136° - 138° C./0.15mm.

1-morpholinocarbonyl-4(5)-butylimidazole, b.p. 126° - 127° C./0.02 mm.1-(N-methyl-N-butylcarbamoyl)-4(5)-tert.butylimidazole, b.p. 152° - 154°C./2.0 mm.

1-(N-methyl-N-pentylcarbamoyl)-4(5)-tert.butylimidazole, b.p. 160° -162° C./2.0 mm.

1-(N-methyl-N-hexylcarbamoyl)-4(5)-tert.butylimidazole, b.p. 170° - 172°C./2.0 mm.

1-piperidinocarbonyl-4(5)-isopropylimidazole, b.p. 170° - 175° C./3.0mm.

1-piperidinocarbonyl-4(5)-sec.butylimidazole, b.p. 190° C./8 mm.

1-pyrrolidinylcarbonyl-4(5)-sec.butylimidazole, b.p. 208° C./22 mm.

1-diethylcarbamoyl-4(5)-sec.butylimidazole, b.p. 165° C./6 mm.

1-(N-methyl-N-ethylcarbamoyl)-4(5)-isopropylimidazole, b.p. 160° - 164°C./9.0 mm.

1-morpholinocarbonyl-4-(5)-isopropylimidazole, b.p. 180° - 185° C./5.0mm.

1-dimethylthiocarbamoyl-4(5)-(1-methylbutyl)imidazole b.p. 180° - 185°C./5.5 mm.

1-dimethylthiocarbamoyl-4(5)-(1-methylbutyl)imidazole b.p. 165° - 170°C./4 mm.

1-(N-methyl-N-ethylcarbamoyl)-4(5)-sec.butylimidazole, b.p. 178° C./28mm.

1-(N-methyl-N-ethylthiocarbamoyl)-4(5)-sec.butylimidazole b.p. 182° C./7mm.

1-dimethylcarbamoyl-4(5)-(1,2-dimethylbutyl)imidazole, b.p. 125° C./0.15mm.

1-dimethylcarbamoyl-4(5)-(1-methylheptyl) imidazole, b.p. 125° C./0.02mm.

1-dimethylcarbamoyl-4(5)-(1-methylpentyl)imidazole, b.p. 128° C./0.5 mm.

1-morpholinocarbonyl-4(5)-isopropylimidazole, b.p. 124° C./0.14 mm.

1-dimethylthiocarbamoyl-4(5)-tert.pentylimidazole, b.p. 180° - 185°C./6.0 mm.

1-(N-methyl-N-2-methoxyethylcarbamoyl)-4(5)-tert.butylimidazole, b.p.116° - 118° C./0.2 mm.

1-(N-methyl-N-3-ethoxypropylcarbamoyl)-4(5)-tert.butylimidazole, b.p.132° - 134° C./0.3 mm.

1-(N-methyl-N-3-ethoxypropylcarbamoyl)-4(5)-sec.butylimidazole, b.p.131° - 132° C./0.15 mm.

1-(N-methyl-N-2-ethoxyethylcarbamoyl)-4(5)-sec.butylimidazole, b.p.140° - 144° C./0.4 mm.

1-dimethylcarbamoyl-4(5)-(1-methylnonyl)imidazole, b.p. 135° C./0.04 mm.

1-dimethylcarbamoyl-4(5)-(1-butylpentyl)imidazole, b.p. 135° C./0.05 mm.

1-dimethylcarbamoyl-4(5)-(1-ethylpentyl)imidazole, b.p. 125° - 130°C./0.2 mm.

1-(N-methyl-N-ethylthiocarbamoyl)-4(5)-tert.butylimidazole, b.p. 118° -121° C./0.2 mm.

1-(N-methyl-N-3-methoxypropylcarbamoyl)-4(5)-tert.butylimidazole, b.p.116° - 122° C./0.2 mm.

The current state of our knowledge indicates that the above compoundswere obtained predominantly or substantially as the 4-substitutedcompounds.

EXAMPLE 7

To a stirred solution of 14 g. 4-tert.pentylimidazole in 100 ml. drytetrahydrofuran and 28 ml. triethylamine was gradually added 13 g.dimethylcarbamoyl chloride. When addition of the carbamoyl chloride wascomplete the reaction mixture was boiled under reflux with stirring forone hour, then cooled to room temperature and poured on to 500 g. waterand crushed ice. After extraction with ether, the ether layer wasseparated, washed with water and dried over anhydrous magnesiumsulphate. The ether was evaporated and a residue remained which wascrystallized from petroleum ether (b.p. 60° - 80° C.) to give theproduct, 1-dimethylcarbamoyl-4(5)-tert.pentylimidazole, m.p. 60° - 61°C. The current state of our knowledge indicates that this compound is1-dimethylcarbamoyl-4-tert.pentylimidazole.

The 4-tert.pentylimidazole used in the above reaction was prepared inthe following way:

A solution of 121.5 g. bromine in 150 ml. chloroform was added dropwisewith stirring to a solution of 87 g. 3,3-dimethylpentan-2-one in 360 ml.methanol. The reaction was initiated by the addition of a few drops ofbromine solution at 15° C., then cooled to 0° C. and addition of brominecontinued whilst the temperature was maintained at 0° - 5° C. Aftercompletion of the bromine addition the reaction mixture was stirred at0° - 5° C. for ten minutes, then poured on to a mixture of crushed iceand water. The water layer was extracted with methylene dichloride andthe extract added to the organic portion. The combined liquors werewashed with water, saturated solution of sodium bicarbonate and thendried over calcium chloride. After evaporating the solvent under reducedpressure, 1-bromo-3,3-dimethylpentan-2-one distilled over, b.p. 84° C./9mm.

A mixture of 111.5 g. 1-bromo-3,3-dimethylpentan-2-one and 300 ml.formamide was heated with stirring. A weak stream of ammonia was passedthrough the reaction mixture over a period of one hour, the temperaturebeing maintained at from 140° - 160° C. The stream of ammonia was thenstopped and the reaction mixture maintained at a temperature of 160° C.for 2 hours. Excess of formamide was evaporated under reduced pressure,the residue diluted with a little warm water and basified with potassiumcarbonate. The imidazole was separated with ether, the ethereal extractbeing washed with water and dried over anhydrous sodium sulphate.

After evaporating the solvent under reduced pressure, the residue wasdistilled to give the product, 4-tert.pentylimidazole, b.p. 114° - 116°C./0.2 mm. On standing this liquid solidified and the solid crystallizedfrom petroleum ether (b.p. 60° - 80° C.) to give a pure product having amelting point of 95° - 96° C.

In an analogous way to that described above, the following compoundswere prepared.

1-dimethylcarbamoyl-4(5)-neopentylimidazole, m.p. 63° - 66° C.

1-dimethylcarbamoyl-4(5)-(2, 3, 3-trimethyl-but-2'-yl)imidazole, m.p.70° - 71° C.

1-morpholinocarbonyl-4(5)-tert.pentylimidazole, m.p. 98° - 99° C.

1-pyrrolidinylcarbonyl-4(5)-tert.pentylimidazole, m.p. 109° - 110° C.

1-dimethylcarbamoyl-4(5)-(1,1,2-trimethylpropyl)imidazole, m.p. 85° -86° C.

1-(n-ethyl-N-methylcarbamoyl)-4(5)-tert.pentylimidazole, m.p. 38° - 40°C.

1-morpholinocarbonyl-4(5)-(2, 3, 3-trimethylbut-2'-yl)imidazole, m.p.122° - 123° C.

1-(4-methylpiperidinocarbonyl)-4(5)-tert.butylimidazole, m.p. 87° C.

1-(n-methyl-N-isopropylcarbamoyl)-4(5)-tert.butylimidazole, m.p. 72° -73° C.

1-(n-methyl-N-2-chloroethylcarbamoyl)-4(5)-tert.butylimidazole, m.p.84° - 85° C.

1-pyrrolidinylcarbonyl-4(5)-isopropylimidazole, m.p. 70° - 71° C.

The current state of our knowledge indicates that the above imidazoleswere obtained predominantly or substantially as the 4-substitutedcompounds.

In the course of preparing the above compounds the following novelintermediates were made.

4-(2, 3, 3-trimethyl-but-2-yl)imidazole, m.p. 149° - 150° C.

4-(1,1,2-trimethylpropyl)imidazole, b.p. 110° - 114° C./0.1 mm.

4-neopentylimidazole, b.p. 106° - 114° C./0.15 - 0.19 mm.

EXAMPLE 8

To a stirred solution of 1.25 g. 2-methyl-4-tert.butylimidazole in 10ml. tetrahydrofuran and 2 ml. triethylamine was added 1.2 g.dimethylcarbamoyl chloride. The resulting mixture was boiled underreflux with stirring for 31/2 hours and then cooled to room temperature.The reaction mixture was diluted with 100 ml. methylene chloride, washedwith water, and the methylene chloride solution dried over magnesiumsulphate. After evaporating the solvent the residue was distilled underreduced pressure to give1-dimethylcarbamoyl-2-methyl-4(5)-tert.butylimidazole, b.p. 126° - 127°C./1 mm. This liquid solidified on standing and when recrystallized frompetroleum ether (b.p. 60° - 80° C.) gave the pure product, m.p. 80° -81° C. The current state of our knowledge indicates that this compoundis 1-dimethylcarbamoyl-2-methyl-4-tert.butylimidazole.

The imidazole used in the above reaction was prepared in the followingway.

85 g. Bromopinacolone was added to a solution of 72 g. potassium acetatein 700 ml. methanol and the resulting mixture was refluxed on a steambath for two hours. It was then cooled, filtered and the filtrate addedwith stirring to a solution of 190 g. cupric acetate monohydrate in 800ml. water and 1000 ml. 25 percent ammonia. A solution of 26 g.acetaldehyde in 200 ml. water was then added to the mixture which washeated on a steam bath for 5 hours with constant stirring.

After cooling the cuprous salt of the imidazole was collected, washedwith water and suspended in 500 ml. of 4N acetic acid. While stirring, asolution of 78 g. potassium ferricycanide in 240 ml. water was added andthe precipitated copper complex removed and washed well with water. Thecombined supernatant liquors were basified to pH 9 - 10 with 5N sodiumhydroxide and extracted several times with ether. The ethereal extractswere combined, washed with water and dried over anhydrous sodiumsulphate. After evaporation of the solvent under reduced pressure theresidue distilled to give the imidazole product, b.p. 112° - 114°C./0.05 mm. This solidified on standing and was recrystallized from amixture of petroleum ether (60° - 80° C.) containing a few drops ofethanol to give 2-methyl-4-tert.butylimidazole, m.p. 155° - 156° C.

In an analogous way to that described above, the following compoundswere prepared.

1-dimethylcarbamoyl-2-ethyl-4(5)-tert.butylimidazole, b.p. 108° - 109°C./0.7 mm.

1-morpholinocarbonyl-2-ethyl-4(5)-tert.butylimidazole, b.p. 124° - 126°C./0.15 mm.

1-dimethylcarbamoyl-2-isopropyl-4(5)-tert.butylimidazole, b.p. 86°C./0.1 mm., m.p. 57° - 58° C.

1-dimethylcarbamoyl-2-butyl-4(5)-tert.butylimidazole, b.p. 108° - 110°C./0.2 mm.

1-morpholinocarbonyl-2-butyl-4(5)-tert.butylimidazole, b.p. 138° - 141°C./0.4 mm.

1-dimethylcarbamoyl-2-isobutyl-4(5)-tert.butylimidazole, b.p. 106° -108° C./0.25 mm.

1-dimethylcarbamoyl-2-(1-methylbutyl)-4(5)-tert.butylimidazole, b.p.98° - 100° C./0.15 mm.

1-dimethylcarbamoyl-2-sec.butyl-4(5)-tert.butylimidazole, b.p. 102° -104° C./0.25 mm.

1-dimethylcarbamoyl-2-(2,6-dimethylhept-5-enyl)-4(5)-tert.butylimidazole,b.p. 154° - 156° C./0.4 mm.

1-dimethylcarbamoyl-2-(1-ethylpropyl)-4(5)-tert.butylimidazole, b.p.97° - 98° C./0.15 mm.

1-(N-methyl-N-2-ethoxyethylcarbamoyl)-2-methyl-4(5)-tert.butylimidazole,b.p. 115° - 117° C./0.1 mm.

1-(N-methyl-N-propylcarbamoyl)-2-methyl-4(5)-tert.butylimidazole, b.p.108° - 110° C./0.3 mm.

1-dimethylcarbamoyl-2-(1-ethyl-2-methylpropyl)-4(5)-tert.butylimidazole,b.p. 108° - 110° C./0.2 mm.

1-morpholinocarbonyl-2-methyl-4(5)-tert.butylimidazole, m.p. 113° - 114°C.

1-dimethylthiocarbamoyl-2-methyl-4(5)-tert.butylimidazole, m.p. 110° -112° C.

1-pyrrolidinylcarbonyl-2-methyl-4(5)-tert.butylimidazole, b.p. 119° -124° C./0.1 mm.

1-dimethylcarbamoyl-2-propyl-4(5)-tert.butylimidazole, b.p. 102° - 104°C./0.3 mm.

1-(N-methyl-N-ethylcarbamoyl)-2-methyl-4(5)-tert.butylimidazole, b.p.106° - 108° C./0.4 mm.

1-dimethylthiocarbamoyl-2-ethyl-4(5)-sec.butylimidazole, b.p. 120° -122° C./0.1 mm.

1-dimethylcarbamoyl-2-propyl-4(5)-sec.butylimidazole, b.p. 108° - 110°C./0.15 mm.

1-dimethylcarbamoyl-2-ethyl-4(5)-sec.butylimidazole, b.p. 110° - 112°C./0.3 mm.

1-morpholinocarbonyl-2-methyl-4(5)-sec.butylimidazole, b.p. 142° - 145°C./0.1 mm.

1-dimethylthiocarbamoyl-2-methyl-4(5)-sec.butylimidazole, b.p. 130° -134° C./0.3 mm.

1-dimethylcarbamoyl-2-methyl-4(5)-sec.butylimidazole, b.p. 118° - 120°C./0.2 mm.

1-morpholinocarbonyl-2-ethyl-4(5)-sec.butylimidazole, b.p. 134° - 136°C./0.1 mm.

1-dimethylcarbamoyl-2-methyl-4(5)-propylimidazole, b.p. 104° - 107°C./0.1 mm.

1-morpholinocarbonyl-2-methyl-4(5)-propylimidazole, b.p. 128° - 130°C./0.1 mm.

The current state of our knowledge indicates that the above imidazoleswere obtained predominantly or substantially as the 4-substitutedcompounds.

In the course of preparing the above compounds the following novelintermediates were made.

2-ethyl-4-tert.butylimidazole, m.p. 154° - 155° C.

2-isopropyl-4-tert.butylimidazole, m.p. 182° C.

2-butyl-4-tert.butylimidazole, m.p. 70° - 72° C.

2-isobutyl-4-tert.butylimidazole, m.p. 128° - 129° C.

2-(1-methylbutyl)-4-tert.butylimidazole, m.p. 108° - 109° C.

2-sec.butyl-4-tert.butylimidazole, m.p. 136° C.

2-(1-ethylpropyl)-4-tert.butylimidazole, m.p. 145° - 146° C.

2-(1-ethyl-2-methylpropyl)-4-tert.butylimidazole, m.p. 148° C.

2-propyl-4-tert.butylimidazole, m.p. 124° - 125° C.

2-ethyl-4-sec.butylimidazole, b.p. 120° - 122° C./0.25 mm.

2-propyl-4-sec.butylimidazole, b.p. 116° - 118° C./0.15 mm.

2-methyl-4-sec.butylimidazole, m.p. 63° - 65° C.

EXAMPLE 9

This example describes an alternative method of preparing1-dimethylcarbamoyl-4(5)-tert.butylimidazole.

A solution of 6.2 g. tert.butylimidazole (0.05 mole) and 4 g. pyridinein 15 ml. dry tetrahydrofuran was added dropwise to a stirred solutionof 2.5 g. phosgene (0.025 mole) in 25 ml. dry tetrahydrofuran maintainedat a temperature of 0° to 5° C. The mixture was stirred for an hour andfiltered. To the filtrate was gradually added a cold solution of 1.37 g.anhydrous dimethylamine (0.03 mole) in 15 ml. dry tetrahydrofuran at 0°C. The mixture was stirred for two hours at 0° to 5° C., filtered andthe solvent evaporated. The residue distilled under reduced pressure togive a fraction having b.p. 102° C./0.5 mm. which solidified on cooling.After crystallization from petroleum ether (60° - 80° C.) the pureproduct, 1-dimethylcarbamoyl-4(5)-tert.butylimidazole m.p. 85° - 86° C.,was isolated. The current state of our knowledge indicates that thiscompound is 1-dimethylcarbamoyl-4-tert.butylimidazole.

EXAMPLE 10

This example describes an alternative method of preparing1-dimethylcarbamoyl-4(5)-tert.butylimidazole.

A solution of 6.2 g. tert.butylimidazole (0.05 mole) and 16 g. pyridinein 15 ml. dry tetrahydrofuran was added dropwise to a stirred solutionof 5 g. phosgene (0.05 mole) in 50 ml. dry tetrahydrofuran at atemperature of 0° to 5° C. The mixture was stirred for an hour andfiltered. To the filtrate was gradually added a cold solution of 3 g.anhydrous dimethylamine (0.065 mole) in 30 ml. dry tetrahydrofuran at 0°to 5° C. The mixture was stirred for 2 hours at 0° to 5° C., filteredand the solvent evaporated. The residue distilled under reduced pressureto give a fraction having b.p. 102° C./0.5 mm. which solidified oncooling. After crystallization from petroleum ether (60° - 80° C.) thepure product, 1-dimethylcarbamoyl-4(5)-tert.butylimidazole, m.p. 85° -86° C., was isolated. The current state of our knowledge indicates thatthis compound is 1-dimethylcarbamoyl-4-tert.butylimidazole.

EXAMPLE 11

To a stirred solution of 62 g. 4-(1-methylcyclohexyl)imidazole in 85 ml.dry tetrahydrofuran and 56 ml. triethylamine was gradually added 45 g.dimethylcarbamoyl chloride. An exothermic reaction ensued and the rateof addition of dimethylcarbamoyl chloride was adjusted so as to maintaina gentle boiling of the reaction mixture under reflux. When addition ofthe dimethylcarbamoyl chloride was complete, the reaction mixture wasboiled under reflux with stirring for one hour, and then cooled to roomtemperature. The reaction mixture was diluted with 200 ml. water andthen extracted with ether (2 × 200 ml.). The ethereal extracts werecombined, washed with water and dried over anhydrous sodium sulphate.After evaporation the resulting residue was crystallized from lightpetroleum (b.p. 60° - 80° C.) to give the product,1-dimethylcarbamoyl-4(5)-(1-methylcyclohexyl)imidazole, m.p. 72° - 73°C. The current state of our knowledge indicates that this compound is1-dimethylcarbamoyl-4-(1-methylcyclohexyl)imidazole.

The 4-(1-methylcyclohexyl)imidazole used in the above reaction wasprepared in the following way.

A solution of 328 g. bromine in 300 ml. chloroform was added graduallyto a stirred solution of 300 g. 1-methylcyclohexyl methyl ketone in 100ml. methanol. After the addition of a few drops of bromine solution at15° C. the reaction mixture was cooled and maintained between 0° - 5° C.The reaction mixture was stirred for 10 minutes, after the addition ofbromine had been completed, and then poured on to a mixture of crushedice and water. The water layer was separated from the organic liquid andextracted with methylene chloride. The extract and the organic portionwere combined and washed with water followed by a saturated solution ofsodium bicarbonate and then finally with water. After drying overcalcium chloride the liquid was evaporated and distilled to givebromomethyl 1-methylcyclohexyl ketone, b.p. 76° - 78° C./0.1 mm. Hg.

A mixture of 387 g. bromomethyl 1-methylcyclohexyl ketone and 1000 ml.formamide was heated with stirring. A stream of ammonia was passedthrough the reaction mixture over a period of one hour, the mixturebeing maintained at a temperature of 140° - 160° C. After the passage ofammonia had been completed the reaction mixture was heated to 180° -190° C. The reaction mixture was maintained at this temperature for aperiod of two hours. Excess of formamide was evaporated under reducedpressure and the residue diluted with a little warm water and madealkaline with potassium carbonate. The resulting mixture was extractedwith ether. After separation the ethereal extract was washed with water,dried over sodium sulphate, evaporated and distilled to give the novelintermediate 4-(1-methylcyclohexyl)imidazole, b.p. 146° - 148° C./0.2mm. Hg. The distillate crystallized from petroleum ether (b.p. 60° - 80°C.) to give the product, m.p. 73° - 75° C.

In an analogous manner to that described above, there were prepared thefollowing compounds.

1-dimethylcarbamoyl-4(5)-cyclohexylimidazole, m.p. 107° - 108° C.(crystallized from petroleum ether, b.p. 100° - 120° C.)

1-dimethylcarbamoyl-4(5)-(1-methylcyclopentyl)imidazole, m.p. 73° C.(crystallized from petroleum ether, b.p. 60° - 80° C.)

The current state of our knowledge indicates that the 4(5) cycloalkylgroups of the imidazoles listed above are predominantly or substantiallyin the 4-position.

In the course of preparing the above imidazoles, the following novelintermediate was made.

4-(1-methylcyclopentyl)imidazole, m.p. 33° - 35° C; b.p. 136° - 140°C./0.5 mm.

EXAMPLE 12

To a stirred solution of 9.6 g. of 4-(1-methylcyclohexyl)imidazole and14 ml. triethylamine in 80 ml. tetrahydrofuran was gradually added 11.9g. morpholinocarbonyl chloride. An exothermic reaction ensued and therate of addition of dimethylcarbamoyl chloride was adjusted so as tomaintain a gentle boiling of the reaction mixture under reflux. Whenaddition of the morpholinocarbonyl chloride was complete, the reactionmixture was boiled under reflux with stirring for 5 hours, and thencooled to room temperatue. The reaction mixture was diluted with 200 ml.water and then extracted with ether (2 × 200 ml.). The ethereal extractswere combined, washed with water and dried over anhydrous sodiumsulphate. After evaporation the resulting residue was crystallized frompetroleum ether (b.p. 80° - 100° C.) to give the product,1-morpholinocarbonyl-4(5)-(1-methylcyclohexyl)imidazole, m.p. 127° -128° C.

The 4-(1-methylcyclohexyl)imidazole used in the above reaction wasprepared as in Example 11.

In an analogous manner to that described above, there was prepared thefollowing compound.

1-morpholinocarbonyl-4(5)-(1-methylcyclopentyl)-imidazole, m.p. 82° -83° C. (crystallized from petroleum ether, b.p. 60° - 80° C.)

The current state of our knowledge indicates that the 1-methylcycloalkylgroups of the above compounds are in the 4-position.

EXAMPLE 13

In an analogous way to that described in Example 11, there were preparedthe following compounds.

1-piperidinocarbonyl-4(5)-(1-methylcyclohexyl)imidazole, m.p. 85° - 87°C.

1-pyrrolidinylcarbonyl-4(5)-(1-methylcyclohexyl)imidazole, m.p. 110° -111° C.

1-pyrrolidinylcarbonyl-4(5)-(1-methylcyclopentyl) imidazole, m.p. 87° -89° C.

1-piperidinocarbonyl-4(5)-(1-methylcyclopentyl) imidazole, m.p. 77° -79° C.

1-dimethylcarbamoyl-4(5)-(1-methylcyclopentyl) imidazole, m.p. 64° - 65°C.

1-(n-ethyl-N-methylcarbamoyl)-4(5)-(1-methylcyclopentyl) imidazole, m.p.47° - 49° C.

1-dimethylcarbamoyl-4(5)-(1-cyclohexyl-1-methylethyl) imidazole, m.p.112° C.

The current state of our knowledge indicates that the above compoundswere obtained predominantly or substantially as the 4-substitutedcompounds.

EXAMPLE 14

A mixture of 20.1 g. 4-(1,3-dimethylcyclohexyl)imidazole, 150 ml. drytetrahydrofuran, 28 ml. triethylamine and 16.2 g. dimethylcarbamoylchloride were refluxed on a steam bath for an hour and then cooled.Methylene chloride was added and the solution washed with water, thefirst washing being re-extracted with methylene chloride. The methylenechloride extracts were dried over magnesium sulphate solution. Afterfiltration the solution was evaporated to give the product,1-dimethylcarbamoyl-4(5)-(1,3-dimethylcyclohexyl)imidazole, b.p. 138° -140° C./0.08 mm. The current state of our knowledge indicates that thisproduct is predominantly 1-dimethylcarbamoyl-4-(1,3-dimethylcyclohexyl)imidazole.

The 4-(1,3-dimethylcyclohexyl)imidazole used in the above reaction wasprepared in the following way.

A solution of 75 ml. (1.465 mole) bromine in 250 ml. chloroform wasadded dropwise to a stirred solution of 235 g. 1,3-dimethylcyclohexylmethyl ketone in 71 ml. methanol whilst maintaining the temperature of0° - 5° C. (the reaction was started by addition of a few drops ofbromine solution at 15° C. then cooled to 0° C. and continued). Thereaction mixture was stirred at 0° - 5° C. for ten minutes after theaddition of bromine solution was complete, then poured on to crushed iceand water mixture. After extracting the water layer with methylenechloride, the methylene chloride was added to the organic portion andthe mixture washed with water, saturated sodium bicarbonate solution anddried over calcium chloride. The solvent was evaporated and distillationgave bromomethyl-1,3-dimethylcyclohexyl ketone, b.p. 86° - 89° C./0.1mm.

A mixture of 265 g. bromomethyl-1,3-dimethylcyclohexyl ketone and 645ml. formamide was heated with stirring. A weak stream of ammonia waspassed through at 140° C. and the temperature raised from 140° - 160° C.for one hour. The stream of ammonia was then stopped and the reactionmixture heated to 180° - 190° C. for two hours. Excess formamide wasevaporated under reduced pressure, the residue diluted with a littlewarm water and basified with potassium carbonate. The imidazole wasseparated with ether, washed with water and dried over sodium sulphate.After evaporation of the ether, the novel product was distilled over,4-(1,3-dimethylcyclohexyl)imidazole, b.p. 140° - 142° C./0.15 mm.

In an analogous manner to that described above, there were prepared thefollowing compounds.

1-diethylcarbamoyl-4(5)-(1-ethylcyclohexyl)imidazole, b.p. 140° C./0.2mm.

1-morpholinocarbonyl-4(5)-(1,3-dimethylcyclohexyl)imidazole, b.p. 160° -162° C./0.02 mm.

1-dimethylthiocarbamoyl-4(5)-(1-methylcyclohexyl)imidazole, b.p. 210° -214° C./3.0 mm.

1-dimethylthiocarbamoyl-4(5)-(1-methylcyclohexyl)imidazole, b.p. 159° -164° C./0.3 mm.

1-dimethylcarbamoyl-4(5)-(1,3,3,-trimethylcyclohexyl) imidazole, b.p.142° - 144° C./0.1 mm.

1-(N-methyl-N-2-butoxyethylcarbamoyl)-4(5)-(1-methylcyclohexyl)imidazole,b.p. 166° - 175° C./0.6 mm.

1-(N-methyl-N-2-ethoxyethylcarbamoyl)-4(5)-(1-methylcyclohexyl)imidazole,b.p. 210° - 215° C./4.5 mm.

1-(N-methyl-N-2-methoxyethylcarbamoyl)-4(5)-(1-methylcyclohexyl)imidazole,b.p. 146° - 149° C./0.2 mm.

1-(N-methyl-N-3-ethoxypropylcarbamoyl)-4(5)-(1-methylcyclohexyl)imidazole,b.p. 153° - 157° C./0.15 mm.

1-(N-methyl-N-3-methoxypropylcarbamoyl)-4(5)-(1-methylcyclohexyl)imidazole,b.p. 155° - 160° C./0.2 mm.

1-dimethylcarbamoyl-4(5)-(1,4-dimethylcyclohexyl) imidazole, b.p. 146° -148° C./0.15 mm.

The current state of our knowledge indicates that the above compoundswere obtained predominantly or substantially as the 4-substitutedcompounds.

EXAMPLE 15

To a solution of 12.8 g. 2-methyl-4(5)-(1-methylcyclopentyl)imidazole ina mixture of 60 ml. tetrahydrofuran and 20 ml. triethylamine was added10.5 g. dimethylcarbamoyl chloride. The resulting mixture was boiledunder reflux with stirring for 31/2 hours, then cooled and diluted with250 ml. methylene chloride. The solution thus formed was washed withwater and then dried over anhydrous magnesium sulphate. Afterevaporating the solvent, the liquid residue distilled to give theproduct,1-dimethylcarbamoyl-2-methyl-4(5)-(1-methylcyclopentyl)imidazole, b.p.124° - 6° C./0.1 mm. The current state of our knowledge indicates thatthis product was predominantly the 4-substituted derivative,1-dimethylcarbamoyl-2-methyl-4-(1-methylcyclopentyl)imidazole.

The 2-methyl-4(5)-(1-methylcyclopentyl)imidazole used in the abovereaction was prepared in the following way.

42 g. Bromomethyl 1-methylcyclopentyl ketone was added to a solution of31.5 g. potassium acetate in 300 ml. methanol and the resulting mixturewas refluxed on a steam bath for two hours. It was then cooled, filteredand the filtrate added with stirring to a solution of 83 g. cupricacetate monohydrate in a mixture of 500 ml. water and 435 ml. 25 percentammonia. A solution of 18.5 g. acetaldehyde in 100 ml. water was thenadded and the mixture heated on a steam bath for five hours withconstant stirring.

After cooling the cuprous salt of the imidazole was collected, washedwith water and suspended in 270 ml. of 4N acetic acid. While stirring, asolution of 34 g. potassium ferricyanide in 100 ml. water was added, andthe precipitated copper complex removed and washed well with water. Thecombined supernatant liquors were basified to pH 9 - 10 with 5N sodiumhydroxide and extracted several times with ether. The ethereal extractswere combined, washed with water and dried over anhydrous sodiumsulphate. After evaporation of the solvent, the residue was crystallizedfrom acetone to give the novel imidazole,2-methyl-4(5)-(1-methylcyclopentyl)imidazole, m.p. 108° C.

In an analogous manner to that described above, there were prepared thefollowing compounds:

1-dimethylcarbamoyl-2-ethyl-4(5)-(1-methylcyclopentyl) imidazole, b.p.118° - 120° C./0.1 mm.

1-dimethylcarbamoyl-2-propyl-4(5)-(1-methylcyclopentyl) imidazole, b.p.128° - 130° C./0.15 mm.

1-dimethylcarbamoyl-2-methyl-4(5)-(1-methylcyclohexyl) imidazole, b.p.135° - 136° C./0.15 mm.

1-dimethylcarbamoyl-2-ethyl-4(5)-(1-methylcyclohexyl) imidazole, b.p.134° - 136° C./0.1 mm.

1-dimethylcarbamoyl-2-propyl-4(5)-(1-methylcyclohexyl) imidazole, b.p.140° - 142° C./0.1 mm.

1-(N-methyl-N-propylcarbamoyl)-2-methyl-4(5)-(1-methylcyclohexyl)imidazoleb.p. 140° - 144° C./0.2 mm.

1-(N-methyl-N-ethylcarbamoyl)-2-methyl-4(5)-(1-methylcyclohexyl)imidazole,b.p. 133° - 135° C./0.25 mm.

1-dimethylcarbamoyl-2-methyl-4(5)-(1,3,3-trimethylcyclohexyl)imidazole,b.p. 132° - 136° C./0.15 mm.

1-morpholinocarbonyl-2-methyl-4(5)-(1-methylcyclohexyl) imidazole, m.p.134° C.

1-dimethylthiocarbamoyl-2-methyl-4(5)-(1-methylcyclohexyl) imidazole,b.p. 140° - 144° C./0.1 mm.

The current state of our knowledge indicates that these imidazoles wereobtained predominantly or substantially as the 4-substituted compounds.

In the course of preparing the above imidazoles, the following novelintermediates were made.

2-ethyl-4-(1-methylcyclopentyl)imidazole, b.p. 128° - 131° C./0.1 mm.,m.p. 87° - 88° C.

2-propyl-4-(1-methylcyclopentyl)imidazole, b.p. 132° - 136° C./0.15 mm.

2-methyl-4-(1-methylcyclohexyl)imidazole m.p. 112° - 113° C.

2-ethyl-4-(1-methylcyclohexyl)imidazole b.p. 136° - 138° C./0.15 mm.

2-propyl-4-(1-methylcyclohexyl)imidazole b.p. 140° - 142° C./0.15 mm.

2-methyl-4-(1,3,3-trimethylcyclohexyl)imidazole.

EXAMPLE 16

To a solution of 9.5 g. 2-ethyl-4-cyclopropylimidazole in 50 ml. drytetrahydrofuran and 22 ml. triethylamine was added 8 g.dimethylcarbamoyl chloride. The resulting mixture was boiled underreflux for 31/2 hours, then cooled and diluted with 250 ml. methylenechloride. After washing with water, the methylene chloride solution wasdried over magnesium sulphate. Evaporation of the solvent gave a residuewhich distilled under reduced pressure to give the product,1-dimethylcarbamoyl-2-ethyl-4(5)-cyclopropylimidazole, b.p. 118° - 119°C./0.2 mm.

The current state of our knowledge indicates that this compound is1-dimethylcarbamoyl-2-ethyl-4-cyclopropylimidazole.

The imidazole reactant was prepared in the following way.

110 g. Cyclopropane carbonylchloride dissolved in 150 ml. of absoluteether was added dropwise into an ice-cold solution of 91 g. diazomethanein 1500 ml. ether. After the addition was complete the temperature ofthe solution was allowed to rise to room temperature and to stand overnight. The removal of the ether by distillation under reduced pressureleft a yellow oil which was carefully mixed with 2000 ml 2N sulphuricacid whilst cooling. This mixture was stirred at 50° C. for 5 hours andwas then cooled, neutralised with solid potassium carbonate andextracted with ether. The ethereal extract was evaporated the residuebeing distilled under reduced pressure to give cyclopropyl hydroxymethylketone, b.p. 56° - 60° C./10 mm.

A solution of 40 g. cyclopropyl hydroxymethyl ketone in 350 ml. methanolwas added with stirring to a solution of 160 g. cupric acetatemonohydrate in 840 ml. water and 840 ml. 25 percent ammonia, followed bythe addition of 28 g. propionaldehyde. The resulting mixture was heatedon a steam bath for five hours with constant stirring. Precipitation ofthe cuprous salt occurred and, after cooling, the precipitate wascollected, washed with water and suspended in 450 ml. 4N-acetic acid.While stirring, a solution of 66.5 g potassium ferricyanide in 200 mlwater was added. The precipitated copper complex was removed and washedwith water. The combined supernatant liquors were basified to pH 9 with5N sodium hydroxide and extracted several times with ether. Aftercombining the ethereal extracts, washing with water and drying oversodium sulphate, the solvent was evaporated. On standing the residuesolidified and was crystallized from petroleum ether to give the novel4-cyclopropyl-2-ethylimidazole, m.p. 104° - 106° C.

EXAMPLE 17

5.1 ml. Dimethylcarbamoyl chloride in 20 ml. dry dioxan was added to amixture of 9.2 g. 2-ethylthio-4-tert.butylimidazole and 8.4 ml.triethylamine in 30 ml. dry dioxan. After heating the mixture on a steambath for 24 hours, the triethylamine hydrochloride was removed and theproduct, 1-dimethylcarbamoyl-2-ethylthio-4(5)-tert.butylimidazole,distilled. It had a boiling point of 108°-111° C. at 0.10-0.12 mm. Hg.and on cooling crystallised to a solid with a melting point of 45° C.The present state of our knowledge indicates that this is the4-substituted compound.

The 2-ethylthio-4-tert.butylimidazole employed in the above reaction wasprepared in the following way.

104 g. Potassium phthalimide was suspended in a solution of 100 g.bromopinacolone in 300 ml. dry toluene. This reaction mixture wasstirred on a steam bath for 18 hours and the solid precipitate filteredoff and washed with toluene. The washings were added to the filtratewhich was heated on a steam bath in vacuo. The product,3,3-dimethyl-1-phthalimidobutan-2-one, crystallised out on cooling. Itwas washed with light petroleum (b.p. 80°-100° C.) and its melting pointwas 97°-101.5° C. 82.6 g. 3,3-Dimethyl-1-phthalimidobutan-2-one wasrefluxed for 10 hours with a mixture of 460 ml. concentratedhydrochloric acid, 400 ml. water and 324 ml. acetic acid. The mixturewas taken to dryness by means of a rotatory evaporator after which 360ml. water was added and the solution chilled in ice. Phthalic acid wasfiltered off and the solution again taken to dryness, the residual solidbeing dissolved in warm absolute alcohol. Ether was added to the cooledsolution and 1-amino-3,3-dimethylbutan-2-one hydrochloride precipitatedas product, melting point 199°-200° C.

35.2 g. 1-Amino-3,3-dimethylbutan-2-one hydrochloride and 30 g.potassium thiocyanate in 50 ml. water was warmed on the steam bath fortwo hours. After cooling, the solid formed was collected, washed withwater, dried and recrystallised from industrial methylated spirit togive 4-tert.butylimidazole-2-thiol, melting point 232°-234° C. Asolution/suspension of this in industrial methylated spirit was added toa solution of 4.5 g. sodium hydroxide in 100 ml. water. 17.6 g. Ethyliodide was added forming a lower layer and the mixture was shaken fortwo minutes whilst the ethyl iodide reacted and dispersed. After 20minutes the alkali was neutralised by passing in carbon dioxide and themethylated spirit removed by evaporation. The solid was collected,washed with water, dried and on recrystallisation from toluene gave2-ethylthio-4-tert.butylimidazole, melting point 116.5°-120° C.

EXAMPLE 18

1.2 g. Sodium hydride in oil (50 percent dispersion) was added to 3.4 g.2-methylthio-4-tert.butylimidazole in dry tetrahydrofuran. When theevolution of hydrogen had ceased, 2.7 g. dimethylcarbamoyl chloride wascarefully added. Heat was evolved and a precipitate formed. After aperiod of an hour the solid was removed and the product distilled. Itwas 1-dimethylcarbamoyl-2-methylthio-4(5)-tert.butylimidazole, boilingpoint 107° C. at 0.07 mm. Hg. pressure. The present state of ourknowledge indicates that this is the 4-substituted compound.

The imidazole reactant used in the above preparation was prepared in ananalogous way to that of 2-ethylthio-4-tert.butylimidazole described inExample 17.

EXAMPLE 19

The following compounds are prepared in an analogous way to thatdescribed in Example 17.

1-dimethylcarbamoyl-2-benzylthio-4(5)-tert.butylimidazole, m.p. 65°-67°C.

1-dimethylcarbamoyl-2-(4-chlorobenzylthio)-4(5)-tert.butylimidazole,m.p. 96°-97° C.

1-dimethylcarbamoyl-2-propylthio-4(5)-tert.butylimidazole, m.p. 69°-71°C.

1-diethylcarbamoyl-2-methylthio-4(5)-tert.butylimidazole, b.p. 114°-116°C./0.1 mm.

1-morpholinocarbonyl-2-methylthio-4(5)-tert.butylimidazole m.p. 70°-72°C.

1-dimethylcarbamoyl-2-isopropylthio-4(5)-tert.butylimidazole, m.p.64°-66° C.

1-dimethylcarbamoyl-2-allylthio-4(5)-tert.butylimidazole, m.p. 65°-67°C.

1-dimethylcarbamoyl-2-n.pentylthio-4(5)-tert.butylimidazole, b.p.132°-136° C./0.08 mm.

1-dimethylcarbamoyl-2-n.butylthio-4(5)-tert.butylimidazole, b.p.126°-128° C./0.8 mm.

1-dimethylcarbamoyl-2-ethylthio-4(5)-sec.butylimidazole, b.p. 103°C./0.08 mm.

1-dimethylcarbamoyl-2-methylthio-4(5)-sec.butylimidazole, b.p. 100°C./0.05 mm.

1-dimethylcarbamoyl-2-propylthio-4(5)-sec. butylimidazole, b.p.108°C./0.06 mm.

1-dimethylcarbamoyl-2-ethylthio-4(5)-isopropylimidazole, b.p. 115°C./0.11 mm.

1-dimethylcarbamoyl-2-methylthio-4-(5)-isopropylimidazole, b.p.116°-120° C./0.65 mm.

1-dimethylcarbamoyl-2-methylthio-4(5)-(1-methylcyclohexyl) imidazole,m.p. 75°-76° C.

1-dimethylcarbamoyl-2-ethylthio-4(5)-(1-methylcyclohexyl) imidazole,m.p. 114°-117° C.

1-dimethylcarbamoyl-2-propylthio-4(5)-(1-methylcyclohexyl) imidazole,m.p. 62°-64° C.

1-dimethylcarbamoyl-2-methylthio-4(5)-(1-ethylpropyl) imidazole, b.p.120°-122° C./0.15 mm.

1-dimethylcarbamoyl-2-ethylthio-4(5)-(1-ethylpropyl) imidazole, b.p.120°-122° C./0.15 mm.

1-(N-methyl-N-ethylcarbamoyl)-2-ethylthio-4(5)-tert.butylimidazole, m.p.93°-94° C.

1-dimethylcarbamoyl-2-ethylthio-4(5)-cyclohexylimidazole, m.p. 148° C.

1-dimethylcarbamoyl-2-ethylthio-4(5)-(1-methylcyclopentyl) imidazole,b.p. 126°-128° C./0.05 mm.

1-dimethylcarbamoyl-2-(2-methylallylthio)-4(5)-tert.butylimidazole, b.p.116°-118° C./0.1 mm.

1-dimethylthiocarbamoyl-2-ethylthio-4(5)-(1-methylcyclohexyl)imidazole,b.p. 180°-190° C./0.2 mm.

1-morpholinocarbonyl-2-ethylthio-4(5)-(1-methylcyclohexyl)imidazole,b.p. 186°-188° C./0.2 mm.

1-dimethylcarbamoyl-2-ethylthio-4(5)-tert.pentylimidazole, b.p.114°-116° C./0.1 mm.

1-piperidinocarbonyl-2-ethylthio-4(5)-tert.butylimidazole, m.p. 63°-65°C.

1-(n-methyl-N-2-methoxyethylcarbamoyl)-2-ethylthio-4(5)-tert.butylimidazole.

1-dimethylthiocarbamoyl-2-ethylthio-4(5)-tert.butylimidazole

1-pyrrolidinylcarbonyl-2-ethylthio-4(5)-tert.butylimidazole

1-dimethylcarbamoyl-2-(2,4-dichlorobenzylthio)-4(5)-tert.butylimidazole

1-(N-methyl-N-propylcarbamoyl)-2-ethylthio-4(5)-sec.butylimidazole

1-(N-methyl-N-ethylcarbamoyl)-2-methylthio-4(5)-sec.butylimidazole

1-dimethylthiocarbamoyl-2-allylthio-4(5)-sec.butylimidazole

1-dimethylthiocarbamoyl-2-benzylthio-4(5)-sec.butylimidazole

1-(N-methyl-N-allylcarbamoyl)-2-ethylthio-4(5)-tert.butylimidazole

1-dimethylcarbamoyl-2-propylthio-4(5)-isopropylimidazole

1-(N-methyl-N-2-ethoxyethylcarbamoyl)-2-methylthio-4(5)-(1-methylcylcohexyl)imidazole

1-(N-methyl-N-2-ethoxyethylcarbamoyl)-2-allylthio-4(5)-sec.butylimidazole

1-diallylcarbamoyl-2-ethylthio-4(5)-tert.butylimidazole

Intermediates

In the course of preparing the above compounds the following imidazoleintermediates were isolated. They were prepared in a way similar to thatdescribed for the preparation of 2-ethylthio-4-tert.butylimidazole inExample 17.

2-benzylthio-4-tert.butylimidazole, m.p. 133° C.

2-(4-chlorobenzylthio)-4-tert.butylimidazole, m.p. 176° C.

2-propylthio-4-tert.butylimidazole, m.p. 101°-103° C.

2-methylthio-4-tert.butylimidazole, m.p. 149°.

2-isopropylthio-4-tert.butylimidazole, m.p. 160°-162° C.

2-allylthio-4-tert.butylimidazole, m.p. 118°-119° C.

2-n.pentylthio-4-tert.butylimidazole, m.p. 96°-98° C.

2-n.butylthio-4-tert.butylimidazole, m.p. 79°-80° C.

2-ethylthio-4-sec.butylimidazole, b.p. 115° C/0.16 mm.

2-methylthio-4-sec.butylimidazole, m.p. 74° C.

2-propylthio-4-sec.butylimidazole, b.p. 106° C/0.04 mm.

2-ethylthio-4-isopropylimidazole, m.p. 96°-98° C.

2-methylthio-4-isopropylimidazole, m.p. 96°-98° C.

2-methylthio-4-(1-methylcyclohexyl)imidazole, b.p. 126°-130° C/0.1 mm.

2-ethylthio-4-(1-methylcyclohexyl)imidazole, m.p. 74°-75° C.

2-propylthio-4-(1-methylcyclohexyl)imidazole, m.p. 105°-106° C.

2-methylthio-4-(1-ethylpropyl)imidazole, b.p. 116°-118° C/0.2 mm.

2-ethylthio-4-(1-ethylpropyl)imidazole, b.p. 118°-120° C/0.1 mm.

2-ethylthio-4-cyclohexylimidazole, m.p. 110°-111° C.

2-ethylthio-4-(1-methylcyclopentyl)imidazole, m.p. 69°-70° C.

2-(2-methylallylthio)-4-tert.butylimidazole, m.p. 104°-105° C.

2-ethylthio-4-tert.pentylimidazole, m.p. 85° C.

The following intermediates were prepared in a similar way to thatdescribed in Example 17.

4-sec.butylimidazole-2-thiol, m.p. 109°-112° C.

4-isopropylimidazole-2-thiol, m.p. 147°-150° C.

4-(1-methylcyclohexyl)imidazole-2-thiol, m.p. 205° C.

4-(1-ethylpropyl)imidazole-2-thiol, m.p. 171° C.

4-cyclohexylimidazole-2-thiol, m.p. 260°-261° C.

4-(1-methylcyclopentyl)imidazole-2-thiol, m.p. 182°-183° C.

4-tert.pentylimidazole-2-thiol, m.p. 174° C.

EXAMPLE 20

To a stirred solution of 11.3 g. 2-methoxymethyl-4-tert.butylimidazolein 30 ml. tetrahydrofuran and 20 ml. triethylamine was added 8 g.dimethylcarbamoyl chloride. The resulting mixture was boiled underreflux for three hours and then diluted with methylene chloride, washedwith water and the methylene chloride solution then dried over magnesiumsulphate. Evaporation of the solvent left a residue which distilledunder reduced pressure to give the product,1-dimethylcarbamoyl-2-methoxymethyl-4(5)-tert.butylimidazole, b.p.106°-108° C./0.1 mm. The present state of knowledge indicates that thisis the 4-substituted compound.

The imidazole reactant used in the above preparation was prepared in thefollowing way.

To a solution of 123 g. potassium acetate in 1200 ml. methanol was added143 g. bromopinacolone. This reaction mixture was refluxed for twohours, then cooled and filtered. The filtrate was added with stirring toa solution of 320 g. cupric acetate monohydrate in 1600 ml. 25 percentammonia and 1400 ml. water, followed by addition of 100 g. 77 percentaqueous solution of methoxyacetaldehyde. The temperature of the reactionmixture was maintained at 30°-40° C. for an hour and the mixture thenheated on a steam bath for a further four hours. After coolingovernight, the insoluble copper salt was collected, washed with waterand suspended in 500 ml. of 4N-acetic acid. A solution of 133 g.potassium ferricyamide in 400 ml. water was added and the precipitatedcopper complex removed and washed with water. The combined supernatantliquors were basified (pH. 9-10) with 5N-sodium hydroxide and extractedwith ether. The etheral extracts were combined, washed with water anddried over magnesium sulphate. The solvent was evaporated and theresidue crystallised from petroleum ether (b.p. 60°-80° C.) to give theproduct, 2-methoxymethyl-4-tert.butylimidazole, m.p. 65°-66° C.

The following compounds were prepared in an analogous manner.

1-dimethylcarbamoyl-2-methoxymethyl-4(5)-sec.butylimidazole, b.p.108°-110° C./0.01 mm.

1-dimethylcarbamoyl-2-methoxymethyl-4(5)-(1-ethylpropyl) imidazole, b.p.118°-120° C./0.1 mm.

1-dimethylcarbamoyl-2-methoxymethyl-4(5)-(1-methylcyclohexyl) imidazole,b.p. 145°-146° C./0.1 mm.

1-dimethylcarbamoyl-2-methoxymethyl-4(5)-(1-methylcyclopentyl)imidazole, b.p. 132°-134° C/0.2 mm.

1-morpholinocarbonyl-2-methoxymethyl-4(5)-(1-methylcylcopentyl)imidazole, m.p. 150°-152° C.

1-(n-methyl-N-ethylcarbamoyl)-2-methoxymethyl-4(5)-tert.butylimidazole,b.p. 112°-114° C/0.2 mm.

1-(N-methyl-N-ethylcarbamoyl)-2-methoxymethyl-4(5)-sec.butylimidazole,b.p. 116°-118° C/0.25 mm.

1-dimethylcarbamoyl-2-methoxymethyl-4(5)-tert.pentylimidazole, b.p. 115°C/0.2 mm.

1-morpholinocarbamoyl-2-methoxymethyl-4(5)-tert.pentylimidazole, b.p.138°-140° C/0.1 mm.

1-morpholinocarbamoyl-2-methoxymethyl-4(5)-tert.butylimidazole, m.p.57°-58° C.

The current state of our knowledge indicates that these imidazoles wereobtained predominantly as the 4-substituted compounds.

The following intermediates were isolated in the course of preparing theabove compounds.

2-methoxymethyl-4-sec.butylimidazole, b.p. 122°-124° C/0.6 mm.

2-methoxymethyl-4-(1-ethylpropyl)imidazole, b.p. 126°-128° C./0.2 mm.

2-methoxymethyl-4-(1-methylcyclohexyl)imidazole, b.p. 142°-144° C./0.5mm.

2-methoxymethyl-4-(1-methylcyclopentyl)imidazole, b.p. 126°-128° C./0.3mm.

2-methoxymethyl-4-tert.pentylimidazole, b.p. 116°-118° C/0.4 mm.

    __________________________________________________________________________                                     Physical State                               R.sup.1                                                                            R.sup.2                                                                            R.sup.3    R.sup.4     and Constant                                 __________________________________________________________________________    methyl                                                                             methyl                                                                             propylthio tert.pentyl liquid, 122-124° C/0.1 mm.            methyl                                                                             methyl                                                                             methylthio ethyl       liquid, 100-102° C/0.1 mm.            methyl                                                                             methyl                                                                             but-2-enylthio                                                                           tert.butyl  liquid, 124-128° C/0.1 mm.            methyl                                                                             methyl                                                                             methylthio propyl      liquid, 106-108° C/0.09 mm.           methyl                                                                             ethyl                                                                              ethylthio  tert.butyl  solid, 84-85° C.                      methyl                                                                             propyl                                                                             methylthio tert.butyl  solid, 100° C.                        methyl                                                                             methyl                                                                             methylthio 1-methylbutyl                                                                             liquid, 112° C/0.04 mm.               methyl                                                                             methyl                                                                             methylthio cyclohexyl  solid, 89-90° C.                      methyl                                                                             methyl                                                                             propylthio cyclohexyl  liquid, 156-158° C/0.2 mm.            methyl                                                                             methyl                                                                             butylthio  1-methylcyclohexyl                                                                        solid, 42-44° C.                      methyl                                                                             allyl                                                                              methylthio tert.butyl  liquid, 154° C/1.5 mm.                methyl                                                                             methyl                                                                             2-methylallylthio                                                                        1-methylcyclohexyl                                                                        liquid, 158-160° C/0.2 mm.            methyl                                                                             methyl                                                                             2-methylallylthio                                                                        cyclohexyl  liquid, 166-168° C/0.25 mm.           methyl                                                                             methyl                                                                             isopropylthio                                                                            sec.butyl   liquid, 128° C/0.1 mm.                methyl                                                                             methyl                                                                             allylthio  sec.butyl   liquid, 124-126° C/0.1 mm.            methyl                                                                             methyl                                                                             butylthio  sec.butyl   liquid, 132-136° C/0.1 mm.            methyl                                                                             methyl                                                                             pentylthio sec.butyl   liquid, 135-139° C/0.08 mm.           methyl                                                                             methyl                                                                             methylthio isobutyl    liquid, 124-128° C/0.1- 0.13 mm.      methyl                                                                             methyl                                                                             ethylthio  isobutyl    liquid, 120° C/0.07 mm.               methyl                                                                             methyl                                                                             propylthio 1-ethylpropyl                                                                             liquid, 130-132° C/0.2 mm.            methyl                                                                             methyl                                                                             methylthio methyl      solid, 87-89° C.                      methyl                                                                             methyl                                                                             methylthio 1-methylcyclopentyl                                                                       liquid, 122-124° C/0.1 mm.            methyl                                                                             methyl                                                                             methylthio 1,1,2-trimethylpropyl                                                                     solid, 50-52° C.                      methyl                                                                             methyl                                                                             ethylthio  1,1,2-trimethylpropyl                                                                     liquid, 118-120° C/0.1 mm.            methyl                                                                             methyl                                                                             propylthio 1-methylcyclopentyl                                                                       liquid, 134-136° C/0.05 mm            methyl                                                                             methyl                                                                             methylthio tert.pentyl liquid, 110-112° C/0.1 mm.            methyl                                                                             ethyl                                                                              methylthio 1-methylcyclohexyl                                                                        liquid, 150-160° C/0.3 mm.            methyl                                                                             methyl                                                                             ethoxycarbonyl-                                                                          tert.butyl  liquid, 140-150° C/0.3 mm.                      methylthio                                                          methyl                                                                             methyl                                                                             2-vinyloxyethylthio                                                                      tert.butyl  liquid, 140-142° C/0.15 mm.           methyl                                                                             methyl                                                                             methylthiomethyl-                                                                        tert.butyl  liquid, 150-152° C/0.2 mm.                      thio                                                                methyl                                                                             methyl                                                                             2-chloroprop-2-                                                                          tert.butyl  liquid, 136-140° C/0.2 mm.                      enylthio                                                            methyl                                                                             methyl                                                                             2-dimethylamino-                                                                         tert.butyl  liquid, 138-140° C/0.1 mm.                      ethylthio                                                           methyl                                                                             methyl                                                                             methoxymethylthio                                                                        tert.butyl  liquid, 145-155° C/0.15 mm.           methyl                                                                             methyl                                                                             3-chloroprop-2-                                                                          tert.butyl  liquid, 147-149° C/0.2 mm.                      enylthio                                                            methyl                                                                             methyl                                                                             2-dimethylamino-                                                                         sec.butyl   liquid, 150-152° C/0.1 mm.                      ethylthio                                                           __________________________________________________________________________

    __________________________________________________________________________                             Physical State                                       R.sup.3       R.sup.4    and Constant                                         __________________________________________________________________________    propylthio    tert.pentyl                                                                              solid, 85-85.5° C.                            methylthio    ethyl      solid, 60-61° C.                              but-2-enylthio                                                                              tert.butyl solid, 84-85° C.                              methylthio    propyl     solid, 53° C.                                 ethylthio     tert.butyl solid, 120° C.                                methylthio    1-methylbutyl                                                                            liquid, 118-120° C/0.05 mm.                   methylthio    cyclohexyl solid, 130-131° C.                            propylthio    cyclohexyl solid, 100-101° C.                            butylthio     1-methylcycohexyl                                                                        solid, 80-82° C.                              2-methylallythio                                                                            1-methylcyclohexyl                                                                       solid, 115° C.                                2-methylallylthio                                                                           cyclohexyl solid, 140° C.                                isopropylthio sec.butyl  solid, 103-106° C.                            allylthio     sec.butyl  liquid, 134-136° C/0.8 mm.                    butylthio     sec.butyl  liquid, 138-140° C/0.07 mm.                   pentylthio    sec.butyl  liquid, 155-158° C/0.1 mm.                    methylthio    isobutyl   solid, 60-61° C.                              ethylthio     isobutyl   solid, 66° C.                                 propylthio    1-ethylpropyl                                                                            solid, 65-67° C.                              methylthio    methyl     solid, 88-90° C.                              methylthio    1-methylcyclopentyl                                                                      solid, 71-73° C.                              propylthio    1-methylcyclopentyl                                                                      solid, 59-61° C.                              methylthio    tert.pentyl                                                                              solid, 93-94° C.                              ethoxycarbonylmethylthio                                                                    tert.butyl solid, 77-79° C.                              methylthiomethylthio                                                                        tert.butyl solid, 131-132° C.                            2-chloroprop-2-enylthio                                                                     tert.butyl solid, 116-118° C.                            2-dimethylaminoethylthio                                                                    tert.butyl solid, 66-68° C.                              3-chloroprop-2-enylthio                                                                     tert.butyl solid, 94-96° C.                              2-dimethylaminoethylthio                                                                    sec.butyl  liquid, 140-142° C/0.1 mm.                    __________________________________________________________________________

Intermediates 4-R⁴ -Imidazole-2-thiol were prepared in a similar way tothat described in Example 17.

    ______________________________________                                                        Physical State                                                R.sup.4         and Constant                                                  ______________________________________                                        ethyl           solid, 163-165° C.                                     propyl          solid, 183-184° C.                                     1-methylbutyl   solid, 88-90° C.                                       isobutyl        solid, 185-186° C.                                     methyl          solid, 246° C.                                         1-ethylpropyl   solid, 171° C.                                         ______________________________________                                    

EXAMPLE 22

1.8 g. Of sodium hydride in mineral oil (50 percent dispersion) wasadded gradually to a solution of 5.4 g.4-isopropyl-2-methylthioimidazole in 30 ml. dry tetrahydrofuran. After aperiod of 30 minutes, 5.05 g. morpholinocarbonyl chloride was added.Heat was evolved and the mixture refluxed for an hour. Thetetrahydrofuran was filtered and evaporated to give a residue which oncrystallisation from petroleum ether (b.p. 100°-120° C.) gave theproduct, 1-morpholinocarbonyl-2-methylthio-4(5)-isopropylimidazole, m.p.63°-65° C. The present state of our knowledge indicates that this is the4-substituted compound.

The imidazole reactant used in the above preparation was prepared in thefollowing way.

126 g. 3-Methylbutan-2-one in 600 ml. methanol was treated with 74 ml.bromine which was added dropwise at a temperature of about 10° C. Thesolution was quenched on ice and the bromoketone then separated andwashed with water. The aqueous liquors were extracted with three 50 ml.portions of petroleum ether and the combined bromoketone and petrolportions added to 216 g. potassium phthalimide in 500 ml.dimethylformamide. The mixture was then heated with stirring on a steambath for two hours then filtered to remove insoluble matter and pouredinto three liters of water with stirring. The solid was collected,dried, and recrystallised from industrial methylated spirit,3-methyl-1-phthalimidobutan-2-one, m.p. 98°-99° C.

176.3 g. Of the phthalimidoketone was refluxed for 20 hours with amixture of one liter of concentrated hydrochloric acid, 1020 ml. waterand 710 ml. acetic acid. The solution was evaporated and the residuetaken up in 800 ml. water. After separation of phthalic acid, thesolution was evaporated to dryness. The solid was air-dried to free itfrom excess acid, 1-amino-3-methylbutan-2-one hydrochloride, m.p.155°-158° C.

An aqueous solution of 98.8 g. of the aminoketone and 63.6 g. potassiumthiocyanate was heated on a steam-bath for 21/2 hours. The oil whichdeposited solidified to give 4-isopropylimidazole-2-thiol, m.p.147°-150° C.

A solution of 6.16 g. potassium hydroxide in 50 ml. industrialmethylated spirit was added to 14.2 g. 4-isopropylimidazole-2-thiol in150 ml. industrial methylated spirit, followed by 15.6 g. methyl iodide.The solution was refluxed for 11/2 hours and the solvent thenevaporated. After treating the residue with water the remaining solidwas collected and recrystallised from ethyl acetate. It was2-methylthio-4-isopropylimidazole, m.p. 96°-98° C.

The following compounds of general formula I were prepared in ananalogous manner. The present state of our knowledge indicates that theywere obtained predominantly or entirely as the 4-substituted compounds.

    __________________________________________________________________________                                    Physical State                                R.sup.1 R.sup.2 NCX-                                                                     R.sup.3   R.sup.4    and Constant                                  __________________________________________________________________________    morpholinocarbonyl                                                                       ethylthio tert.pentyl                                                                              solid, 79-80° C.                       morpholinocarbonyl                                                                       propylthio                                                                              tert.pentyl                                                                              solid, 63.5-64.5° C.                   morpholinocarbonyl                                                                       2-methylallylthio                                                                       tert.butyl liquid, 140-142° C/0.1 mm.             morpholinocarbonyl                                                                       methylthio                                                                              cyclohexyl solid, 90-92° C.                       morpholinocarbonyl                                                                       ethylthio cyclohexyl solid, 94-96° C.                       pyrrolidinylcarbonyl                                                                     methylthio                                                                              tert.butyl solid, 99-101° C.                      morpholinocarbonyl                                                                       methylthio                                                                              propyl     solid, 78-80° C.                       morpholinocarbonyl                                                                       methylthio                                                                              sec.butyl  solid, 70-72° C.                       morpholinocarbonyl                                                                       ethylthio sec.butyl  solid, 73-75° C.                       morpholinocarbonyl                                                                       butylthio sec.butyl  liquid, 153-157° C/0.1 mm.             morpholinocarbonyl                                                                       propylthio                                                                              sec.butyl  solid, 34-36° C.                       morpholinocarbonyl                                                                       isopropylthio                                                                           sec.butyl  solid, 44-46° C.                       morpholinocarbonyl                                                                       pentylthio                                                                              sec.butyl  liquid, 161-166° C/0.1 mm.             morpholinocarbonyl                                                                       methylthio                                                                              tert.butyl solid, 95-97° C.                       morpholinocarbonyl                                                                       ethylthio tert.butyl solid, 100-102° C.                     morpholinocarbonyl                                                                       methylthio                                                                              isobutyl   solid, 70-72° C.                       morpholinocarbonyl                                                                       ethylthio isobutyl   solid, 63-65° C.                       morpholinocarbonyl                                                                       ethylthio isopropyl  solid, 59-61° C.                       morpholinocarbonyl                                                                       methyltho isopropyl  solid, 63-65° C.                       morpholinocarbonyl                                                                       ethylthio 1-ethylpropyl                                                                            liquid, 142-145° C/0.2 mm.             morpholinocarbonyl                                                                       propylthio                                                                              1-ethylpropyl                                                                            liquid, 14 148° C/0.15 mm.             morpholinocarbonyl                                                                       methylthio                                                                              1-ethylpropyl                                                                            liquid, 146-148° C/0.2 mm.             morpholinocarbonyl                                                                       methylthio                                                                              methyl     solid, 81-83° C.                       morpholinocarbonyl                                                                       methylthio                                                                              1-methylcyclopentyl                                                                      solid, 90-91° C.                       morpholinocarbonyl                                                                       methylthio                                                                              tert.pentyl                                                                              solid, 85-86° C.                       morpholinocarbonyl                                                                       2-chloroprop-2-                                                                         tert.butyl liquid, 166-168° C/0.25 mm.                       enylthio                                                           morpholinocarbonyl                                                                       methylthiomethyl-                                                                       tert.butyl liquid, 170-172° C/0.2 mm.                        thio                                                               piperidinocarbonyl                                                                       ethylthio tert.butyl solid, 63-65° C.                       morpholinocarbonyl                                                                       2-dimethylamino-                                                                        sec.butyl  liquid, 164-166° C/0.1 mm.                        ethylthio                                                          __________________________________________________________________________

EXAMPLE 23

17.0 g. 2-Methylthio-4-tert.butylimidazole were dissolved in 200 ml. ofdry dioxan. after which 13.9 ml. of triethylamine and 12.3 g.dimethylthiocarbamoyl chloride were added. The mixture was refluxed foreight hours, then cooled and the precipitate of triethylaminehydrochloride filtered off. On distilling off the dioxan a brown oilremained. This oil was extracted with two 50 ml. portions of petroleumether (b.p. 60°-80° C.) and on cooling a solid was deposited which wascollected and recrystallised from petroleum ether (b.p. 80°-100° C.)with charcoal to give1-dimethylthiocarbamoyl-2-methylthio-4(5)-tert.butylimidazole, m.p.94°-96° C. The present state of our knowledge indicates that this is the4-substituted compound.

The following compounds were prepared in an analogous manner.

1-dimethylthiocarbamoyl-2-ethylthio-4(5)-(1-methylcyclohexyl) imidazole,b.p. 180°-190° C/0.2 mm.

1-dimethylthiocarbamoyl-2-methylthio-4(5)-tert.pentylimidazole, b.p.126°-130° C/0.1 mm.

EXAMPLE 24

A solution of 7 g. 2-methylthio-4-tert.butylimidazole in 45 ml. drytetrahydrofuran was added to 2.42 g. sodium hydride in mineral oil (60percent dispersion). The resulting mixture was cooled to a temperatureof between 0° and 5° C. and then 10 g. of1-(N-methyl-N-2-ethoxyethyl)carbamoyl chloride added whilst the reactionmixture was maintained below 5° C. After filtering to remove solidprecipitate the filtrate was refluxed on a steam bath for 2 hours. Ondistillation the product, 1-(N-methyl-N-2-ethoxyethyl)carbamoyl-2-methylthio-4(5)-tert.butylimidazole, was collected, b.p.130°-134° C/0.1 mm. Hg pressure. The present state of our knowledgeindicates that this was predominantly the 4-substituted compound.

The following compound was also prepared by a similar method1-(N-methyl-N-2-ethoxyethyl)carbamoyl-2-methylthio-4(5)-isopropylimidazole,b.p. 132°-134° C/0.1 mm.

EXAMPLE 25

This example illustrates an alternative method of preparing theintermediate 2-methylthio-4-tert.butylimidazole by a route whichcomprises reacting a α-haloketone with an S-alkylisothiouronium salt.

A mixture of 17.9 g. α-bromopinacolone, 16.7 g. S-methyl-iso-thiouroniumsulphate and 32 g. sodium carbonate in 100 ml. water and 100 ml. ethanolwas stirred under reflux for a period of 1 hour. The ethanol wasdistilled off and after the addition of a further quantity of 100 ml.water, 150 ml. toluene was added. The mixture was stirred vigorously forten minutes and the hot toluene separated and washed with 100 ml. hotwater. 70 ml. Of the toluene and traces of water were distilled off andthe remaining toluene solution stirred at 0° C. for 30 minutes whencrystalline 2-methylthio-4-tert.butylimidazole separated. The productwas filtered off, washed with cold toluene and dried, m.p. 149°-150° C.

EXAMPLE 26

A concentrated solution of 1.2 g.1-dimethylcarbamoyl-2-methylthio-4-(5)-tert.butylimidazole in 50 ml.ether was added to a concentrated solution of 1.5 g. flavianic acid in 4l. ether. The flavianic crystallised on standing and was filtered off,m.p. 205°-206° C with decomposition. On recrystallisation fromindustrial methylated spirits a pure sample was obtained, m.p. 206° C.with decomposition.

In a similar manner the following acid addition salts were prepared:

    ______________________________________                                        salt        melting point ° C.                                         ______________________________________                                        bromide     185° C. with decomposition                                 picrate     169-171° C.                                                nitrate     152° C. with decomposition                                 ______________________________________                                    

EXAMPLE 27

An emulsifiable concentrate suitable for dilution with water to form anaqueous emulsion was prepared from the following ingredients:

    ______________________________________                                                                %.sup.w /v                                            ______________________________________                                        Compound of Example 1         20.0                                            Calcium dodecylbenzenesulphonate                                                                            2.0                                             Nonylphenoxypolyethoxyethanol*                                                                              4.0                                             Cyclohexanone                 15.0                                            Xylene                 to     100.0                                           ______________________________________                                         *A nonylphenol-ethylene oxide condensate containing an average of 14 mols     ethylene oxide per mol. nonylphenol.                                     

Similar emulsifiable concentrates were prepared in which the imidazolecompound in the above formulation was replaced by the followingcompounds of Example 3:

1-dimethylthiocarbamoyl-4(5)-tert.butylimidazole

1-(N-methyl-N-ethylcarbamoyl)-4(5)-tert.butylimidazole

1-(N-methyl-N-propylcarbamoyl)-4(5)-tert.butylimidazole

1-dimethylcarbamoyl-2-ethyl-4(5)-methylimidazole

1-dimethylcarbamoyl-4(5)-n-pentylimidazole

EXAMPLE 28

Emulsifiable concentrates suitable for dilution with water to form anaqueous emulsion were prepared from the following ingredients:

    ______________________________________                                                             %.sup.w /v                                               ______________________________________                                        Compound                   25.0                                               Calcium dodecylbenzenesulphonate*                                                                        2.5                                                Nonylphenoxypolyethoxyethanol                                                                            2.5                                                Xylene               to    100.0   % vol                                      ______________________________________                                         *A nonylphenol-ethylene oxide condensate containing an average of 14 mols     ethylene oxide per mol. nonylphenol.                                     

Emulsifiable concentrates containing the following compounds wereprepared.

1-dimethylcarbamoyl-4(5)-isobutylimidazole

1-dimethylcarbamoyl-4(5)-(1-ethylpropyl)imidazole

1-dimethylcarbamoyl-4(5)-sec.butylimidazole

1-dimethylcarbamoyl-4(5)-isopropylimidazole

1-dimethylcarbamoyl-4(5)-sec.butylimidazole

1-dimethylcarbamoyl-4(5)-propylimidazole

1-dimethylcarbamoyl-4(5)-tert.pentylimidazole

1-(N-2-ethoxyethyl-N-methylcarbamoyl)-4(5)-tert.butylimidazole

EXAMPLE 29

Granules containing 5% w/w of the imidazole compound of Example 1 wereprepared by impregnating granules of fuller's earth (mesh size 20/40British Standard Sieve) with a solution of the imidazole compound inxylene and then evaporating the xylene from the impregnated granules.

EXAMPLE 30

Granules containing 5% w/w of the1-dimethylcarbamoyl-4(5)-(1-methylcyclohexyl)imidazole were prepared byimpregnating granules of fuller's earth (mesh size 20/40 BritishStandard Sieve) with a solution of the imidazole compound in xylene andthen evaporating the xylene from the impregnated granules.

EXAMPLE 31

An emulsifiable concentrate suitable for dilution with water to form anaqueous emulsion was prepared from the following ingredients:

    ______________________________________                                        1-dimethylcarbamoyl-4(5)-(1-methylcyclo-                                                            25.0%      .sup.w /v -hexyl)imidazole                   Calcium dodecylbenzenesulphonate                                                                    2.5%       .sup.w /v -Nonylphenoxypolyethoxyethanol*                                     12.5% .sup.w /v -Cyclohexanone 20.0% vol.                                     1                                            Xylene                to 100.0%  vol.                                         ______________________________________                                         *A nonylphenol-ethylene oxide condensate containing an average of 14 mols     ethylene oxide per mol. nonylphenol.                                     

Similar emulsifiable concentrates were prepared in which the imidazolecompound in the above formulation was replaced by the remainingcompounds of the invention described in Example 11.

EXAMPLE 32

A dispersible powder was prepared from the following ingredients:

    ______________________________________                                                              %w.sub./w                                               ______________________________________                                        1-dimethylcarbamoyl-4(5)-(1-methylcyclo-                                                              25.0                                                  hexyl)imidazole                                                               Nonylphenoxypolyethoxyethanol*                                                                        1.0                                                   Dyapol PT*              5.0                                                   Kaolin                  to 100.0                                              ______________________________________                                         *A nonylphenol-ethylene oxide condensate containing an average of 14 mols     ethylene oxide per mol. nonylphenol. Dyapol PT is an anionic dispersant       based on the sodium salt of a sulphonated condensation product of             urea/formaldehyde and cresol.                                            

EXAMPLE 33

Emulsifiable concentrates suitable for dilution with water to form anaqueous emulsion were prepared from the following ingredients:

    ______________________________________                                                                %w.sub./v                                             ______________________________________                                        Active compound         25.0                                                  ,Calcium dodecylbenzenesulphonate                                                                     3.0                                                   Nonylphenoxypolyethoxyethanol*                                                                        3.0                                                   Xylene                  to 100.0% vol.                                        ______________________________________                                         *A nonylphenol-ethylene oxide condensate containing an average of 14 mols     ethylene oxide per mol. nonylphenol.                                     

Emulsifiable concentrates containing the following compounds wereprepared:

1-dimethylcarbamoyl-2-methylthio-4(5)-tert.butylimidazole

1-dimethylcarbamoyl-2-ethylthio-4(5)-tert.butylimidazole

1-dimethylcarbamoyl-2-methoxymethyl-4(5)-tert.butylimidazole

1-morpholinocarbonyl-2-methylthio-4(5)-tert.butylimidazole

EXAMPLE 34

Granules containing 5% w/w of the carbamoylimidazole compounds ofExamples 17 and 18 were prepared by impregnating granules of fuller'searth (mesh size 20/40 British Standard Sieve) with a solution of thecarbamoylimidazole compound in xylene and then evaporating the xylenefrom the impregnated granules.

EXAMPLE 35

Dispersible powders were prepared from the following ingredients:

    ______________________________________                                                                %w/w                                                  ______________________________________                                        Active compound         25.0                                                  Silicic Acid            25.0                                                  Calcium lignosulphonate 10.0                                                  Sodium dioctylsulphosuccinate                                                                         0.5                                                   Kaolin                  to 100.0                                              ______________________________________                                    

Dispersible powders containing the following compounds were prepared:

1-dimethylcarbamoyl-2-methylthio-4(5)-tert.butylimidazole

1-dimethylcarbamoyl-2-ethylthio-4(5)-tert.butylimidazole

1-dimethylcarbamoyl-2-methoxymethyl-4(5)-tert.butylimidazole

1-morpholinocarbonyl-2-methylthio-4(5)-tert.butylimidazole

EXAMPLE 36

Broad bean plants 3 - 5 cm. high were infested with aphids (Megouraviciae) and then sprayed with an aqueous dispersion containing 250 partsper million w/v of the imidazole compound of Example 1. Each plant waskept under a lamp glass for 24 hours and then examined. It was foundthat a complete kill of the aphids had been obtained. The aphidpopulations of control plants that had been treated with an aqueousspray not containing any test compound were not affected.

EXAMPLE 31

Broad bean plants 3 - 5 cm. high were infested with aphids (Megouraviciae) and then sprayed with an aqueous dispersion containing 250 partsper million w/v of each of the carbamoyl imidazole compounds describedin Example 11. Each plant was kept under a lamp glass for 24 hours andthen examined. It was found that all of the compounds completely killoff the aphids. The aphid populations on control plants that had beentreated with an aqueous spray not containing any test compound were notaffected.

EXAMPLE 32

Broad bean plants 3 - 5 cm. high were infested with aphids (Megouraviciae) and then sprayed with an aqueous dispersion containing 250 partsper million w/v of each of the carbamoyl imidazole compounds describedin Examples 2 to 8 and 12 to 16. Each plant was kept under a lamp glassfor 24 hours and then examined. It was found that all of the compoundsgave at least a 50 percent control of the aphid. The aphid populationson control plants that had been treated with an aqueous spray notcontaining any test compound were not affected.

EXAMPLE 33

Hop leaves infested with the hop aphid, Phorodon humuli, were treatedwith aqueous dispersions of various compounds.

Ten leaves were taken from each of four replicate plants and the averagenumber of aphids per leaf calculated. The hop plants were sprayed withan aqueous dispersion of the test compound till run off. Assessment oneday after spraying showed that with an aqueous dispersion containing0.03 percent by weight of the test compound, the following compoundsachieved over 50 percent kill.

1-dimethylcarbamoyl-4(5)-tert.butylimidazole

1-dimethylcarbamoyl-4(5)-isopropylimidazole

1-dimethylcarbamoyl-4(5)-(1-ethylpropyl)imidazole

1-dimethylcarbamoyl-4(5)-sec.butylimidazole

1-dimethylthiocarbamoyl-4(5)-sec.butylimidazole

1-dimethylcarbamoyl-4(5)-propylimidazole

1-dimethylcarbamoyl-4(5)-(1-methylcyclohexyl)imidazole

1-dimethylcarbamoyl-4(5)-tert.pentylimidazole

EXAMPLE 34

An assessment of ovo-larvicidal activity against Tetranychus urticae wasmade in the following way.

Freshly laid eggs of Tetranychus urticae on a French bean leaf disc 2cm. in diameter were sprayed with an aqueous dispersion of the compoundtest. After ten days any live larvae on the leaf disc were counted andthe percentage mortality assessed. Triplicate assessments were made atvarious concentrations of test compound in order to obtain approximatelyLD₅₀ values, expressed as p.p.m. w/v of test compound.

The following two compounds were found to have an LD₅₀ below 250 p.p.m.

1-dimethylcarbamoyl-4(5)-(1-methylcyclopentyl)imidazole

1-dimethylcarbamoyl-4(5)-(1-methylcyclohexyl)imidazole

EXAMPLE 41

An assessment of the activity of1-dimethylcarbamoyl-4(5)-tert.butylimidazole against the green riceleafhopper was made in the following way.

The roots of a rice seedling were dipped in an aqueous emulsioncontaining 0.005% by weight of the test compound. The rice seedling wasenclosed in a glass cylinder into which fifteen adult green riceleafhoppers were inserted and the temperature was maintained at 25° C.After forty-eight hours the insect mortality was observed. It was foundthat a complete kill of the insects had occurred.

EXAMPLE 42

Broad bean plants 3 - 5 cm. high were infested with aphids (Megouraviciae) and then sprayed with an aqueous dispersion containing 250 partsper million w/v of the following compounds:

1-dimethylcarbamoyl-2-methylthio-4(5)-tert.butylimidazole

1-dimethylcarbamoyl-2-ethylthio-4(5)-tert.butylimidazole

1-dimethylcarbamoyl-2-methoxymethyl-4(5)-tert.butylimidazole

1-morpholinocarbonyl-2-methylthio-4(5)-tert.butylimidazole

1-morpholinocarbonyl-2-methylthio-4(5)-isopropylimidazole

Each plant was kept under a lamp glass for 24 hours and then examined.It was found that a complete kill of the aphids had been obtained. Theaphid populations of control plants that had been treated with anaqueous spray not containing any test compound were not affected.

EXAMPLE 43

Broad bean plants 3 - 5 cm. high were infested with aphids (Megouraviciae) and then sprayed with an aqueous dispersion containing 250 partsper million w/v of the carbamoylimidazole compounds of Examples 17, 18and 20-24. Each plant was kept under a lamp glass for 24 hours and thenexamined. It was found that at least 50 percent of the aphids werekilled. The aphid populations of control plants that had been treatedwith an aqueous spray not containing any test compound were notaffected.

EXAMPLE 44

Broad bean plants 3 - 5 cm. high were infested with blackbean aphids(Aphis fabae) and then sprayed with an aqueous dispersion containing 100parts per million w/v of each active compound listed below. The plantswere kept under a lamp glass for 24 hours and then examined. In allcases at least 50 percent of the aphids were killed. The aphidpopulations of control plants that had been treated with an aqueousspray not containing any test compound were not affected.

1-dimethylcarbamoyl-2-methylthio-4(5)-tert.butylimidazole

1-morpholinocarbonyl-2-methylthio-4(5)-tert.butylimidazole

1-morpholinocarbonyl-2-methylthio-4(5)-sec.butylimidazole

1-morpholinocarbonyl-2-methylthio-4(5)-isopropylimidazole

1-morpholinocarbonyl-2-methylthio-4(5)-1-ethylpropylimidazole

1-dimethylcarbamoyl-2-methylthio-4(5)-isobutylimidazole

EXAMPLE 45

The compounds to be tested were applied as soil drenches. 25 ml. Of anaqueous test solution was watered into the soil in an 8 cm. diameterplant pot containing a single broad bean plant. A cardboard shield wasplaced around the plant so that only a part of it protruded. This wasinfested with aphids (Megoura viciae). After three days the aphicidaleffect was assessed by counting the numbers of live and dead aphids.

The following compounds were found to have an LD₅₀ of less than 100p.p.m.

1-dimethylcarbamoyl-2-methylthio-4(5)-tert.butylimidazole

1-dimethylthiocarbamoyl-2-methylthio-4(5)-tert.butylimidazole

1-morpholinocarbonyl-2-methylthio-4(5)-tert.butylimidazole

1-dimethylcarbamoyl-2-allylthio-4(5)-sec.butylimidazole

1-dimethylcarbamoyl-2-ethylthio-4(5)-(1-methylcyclopentyl) imidazole

1-dimethylcarbamoyl-2-but-2-enylthio-4(5)-tert.pentylimidazole

EXAMPLE 46

Ten larvae of the cabbage white butterfly (Pieris brassicae) were placedin a tube together with a square of cabbage leaf which had been dippedin a test solution containing1-dimethylcarbamoyl-2-methylthio-4(5)-tert.butylimidazole and allowed todry. After 24 hours untreated cabbage was added as food and after afurther 24 hours an assessment was made of the mortality of the larvaeby counting the numbers of live and dead insects.

Two replicates were carried out employing a test solution of 200 p.p.m.At this level of concentration the active compound gave greater than 50percent control of the larvae.

We claim:
 1. A compound of the formula ##STR8## in which X is selectedfrom the group consisting of oxygen and sulphur, R³ is selected from thegroup consisting of alkylthio of 1 to 6 carbon atoms optionallysubstituted with at least one substituent selected from the groupconsisting of chloro, bromo, fluoro, methoxy, ethoxy, methoxy carbonyl,ethoxy carbonyl, methylthio, ethylthio, vinyloxy, dimethylamino anddiethylamino, alkenylthio of 2 to 6 carbon atoms optionally substitutedwith one to two halo substituents selected from the group consisting ofbromo, fluoro and chloro, benzylthio optionally substituted with one ormore substituents selected from the group consisting of methyl, nitro,methoxy, trifluoromethyl and chloro, alkoxyalkyl containing 2 to 5carbon atoms, and alkylthioalkyl containing 2 to 5 carbon atoms; R⁴ isselected from the group consisting of alkyl of 1 to 10 carbon atoms andcycloalkyl of 3 to 7 carbon atoms optionally substituted with 1 to 3methyl groups; and R¹ and R², together with the nitrogen atom to whichthey are attached, form a morpholino group optionally containing 1 to 4lower alkyl substituents; and salts thereof of acids selected from thegroup consisting of hydrochloric, hydrobromic, hydroiodic, hydrofluoric,sulphuric, nitric, phosphoric, perchloric, sulphamic, formic, acetic,trichloracetic, oxalic, picric, benzenesulphonic,dodecylbenzenesulphonic, p-toluenesulphonic, stearic, flavianic, embonicand tetraiodophthalic acids.
 2. A compound of the formula ##STR9## inwhich X is selected from the group consisting of oxygen and sulphur; R³is selected from the group consisting of alkylthio of 1 to 6 carbonatoms, alkenylthio of 2 to 6 carbon atoms, benzylthio and alkxoyalkyl of2 to 5 carbon atoms; R⁴ is selected from the group consisting of alkylof 1 to 10 carbon atoms and cycloalkyl of 3 to 7 carbon atoms optionallysubstituted with 1 to 3 methyl groups; and R¹ and R², together with thenitrogen atom to which they are attached, form a morpholino groupoptionally containing 1 to 4 methyl substituents.
 3. A compoundaccording to claim 2 in which X is oxygen.
 4. A compound according toclaim 3 in which R³ is alkylthio of 1 to 4 carbon atoms.
 5. A compoundaccording to claim 4 in which R⁴ is selected from the group consistingof tert. butyl, sec. butyl, propyl, 1-ethylpropyl, isopropyl andtert.pentyl. 6.1-morpholinocarbonyl-2-methylthio-4(5)-tert.butylimidazole.
 7. Aninsecticidal composition which comprises an insecticidally effectiveamount of a compound according to claim 1, together with a suitablecarrier.
 8. An insecticidal composition which comprises aninsecticidally effective amount of a compound according to claim 2together with a suitable carrier.
 9. A method of combating insects whichcomprises applying to said insects or the locus thereof aninsecticidally effective amount of a compound according to claim
 1. 10.A method of combating insects which comprises applying to said insectsor the locus thereof an insecticidally effective amount of a compoundaccording to claim 2.